Kras degrader. Etsuko Miyamoto-Sato.
Kras degrader KRAS, HRAS and NRAS protein levels were analyzed by western blot after 72 h of dox treatment of the cells at 0. Nagashima, T. Article CAS PubMed PubMed Central Google Scholar Biological Activity for LC 2. Degrading KRAS mutant alleles or KRAS isoform in the case of a pan-KRAS degrader strategy was clinically validated in mice using systemic genetic ablation by the Barbacid lab. Optimized degraders exhibit DC50<1 nMand Dmax>90% for G12D KRAS G12D PROTAC degraders are potent and selective Degradation of KRAS G12D provides an advantage in Abstract. Recent advances Why might a KRAS PROTAC degrader have advantages? Focus on KRAS G12D for this talk. ASP3082, a First-in-class novel KRAS G12D degrader, exhibits remarkable anti-tumor activity in KRAS G12D mutated cancer models. Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models (AACR 2023) - P1 | "ASP3082 is a potential therapeutic agent for patients with tumors harboring the KRAS G12D mutation. Subscribe to our newsletter. Targeting SOS1, a guanine nucleotide exchange factor, has arisen as an attractive approach for KRAS-mutant CRC. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of ARTICLE A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS Nicolas Bery 1,2, Ami Miller1,3 & Terry Rabbitts 1,3 Tumour-associated KRAS mutations are the most A First-Class Degrader Candidate Targeting Both KRAS G12D and G12V Mediated by CANDDY Technology Independent of Ubiquitination. TKD is composed of a KRAS-binding Now, scientists are reporting a compound that eliminates multiple KRas mutants using an alternative strategy—targeted protein degradation. Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. However, because KRAS engagement mediated by co-valent target ligands itself leads to In our study, PROTACs targeting mutant KRAS G12D have been designed and developed. Presented at the 34th EORTC-NCI-AACR Symposium on KRAS is an important and validated target in LUAD, PDAC, and CRC in which it actively participates in tumor initiation and maintenance. Despite of tremendous efforts, it remains a big challenge to develop inhibitors that can target the oncogenic K-Ras mutants, especially mutants without specific active or charged side chains such as K-RasG12V. By employing an MCB-294 derivative as the KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system Major Finding: A small molecule degrader targets 13 of the most common oncogenic KRAS alleles in vitro and in vivo. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic We demonstrate that while the KRAS-specific DARPin degrader induces specific proteolysis of both mutant and wild type KRAS, it only inhibits proliferation of cancer cells expressing mutant KRAS in vitro and in vivo. Oral administration of BTX-10908 resulted in dose-dependent SOS1 degradation and tumor growth inhibition in H358 (KRAS G12C) and H441 (KRAS G12V) xenografts. In the physiological state, when RAS receives an KRAS mutations are the most common oncogenic drivers. 5 μg mL −1 (+) or not induced (− Pan-KRAS degrader: Preclinical: Work disclosed at Dec 2022 R&D day; IND filing is expected by Mar 2024: A2A-03: A2A Pharmaceuticals: Pan-KRAS degrader: Preclinical – Unnamed: Sibylla Biotech: Pan-KRAS Importantly, Boehringer Ingelheim plans to make the KRAS degrader compound ACBI3, freely available for the scientific community through its opnMe® portal, without any strings attached, which could catalyze future The RAS gene family consists of KRAS, HRAS, and NRAS, which encodes membrane-associated 21 kDa proteins with guanosine triphosphatase (GTPase) activity [1,2]. Among KRAS mutations, KRAS G12D is the most frequent driver mutation and is found in approximately 34% of pancreatic ductal adenocarcinoma (PDAC), 10% to 12% of colorectal cancer, 4% of lung adenocarcinoma and also in a subset of other solid tumors. to study the efficacy and safety ACBI3 is a selective, potent and in vivo active pan-KRAS degrader discovered via a structure-based design approach guided by optimization of VHL:PROTAC:KRAS ternary complex stability and durability. Size Price Stock Quantity; 5 mg USD 800: In-stock 10 mg USD 1200: In-stock 25 mg USD 2040: In-stock “Undruggable” targets such as KRAS are particularly challenging in the development of drugs. KRASG12X mutations are identified in approximately 25% of lung cancer, 24% of colorectal (CRC), and 79% of pancreatic ductal adenocarcinoma (PDAC). We performed a comparison of the KRAS-specificity of the KRAS degrader with the pan-RAS degrader in a stably transduced H358 (lung Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue[1][1]. 8 described BI-2865, the first pan-KRAS-selective inhibitor, as well as BI-2493, a close analogue that was used for in vivo studies. 5 × 10 6 H358 cells expressing either FLuc/iDAb RAS-UBOX or FLuc/VHL-DP KRAS were injected subcutaneously into CD-1 nude mice. For research use only. Currently, a phase 1 clinical trial is underway in KRAS gene locates on chromosome 12p12 with the molecular weight of approximately 21 kDa. Clinical trial identification. Early PROTACs recruiting the von Hippel-Lindau (VHL) or cereblon E3 ubiquitin ligases to KRASG12C havebeendisclosedthatarebased on covalent KRAS binders (9, 10). These mutations occur in about 20–30% of all human cancers, Human Health Boehringer Ingelheim is a research-driven group of companies dedicated to the discovery, development, manufacture and marketing of innovative health care products. Here, we Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Pan-KRAS degraders may offer a viable strategy to overcome treatment-induced resistance to variant-specific KRAS inhibitors. (AR) protein degrader luxdegalutamide (ARV-766) for the treatment of prostate cancer. With the advancement of targeted protein degradation technology, this review similarly also focuses on the PROTACs designed for KRAS G12D or pan-KRAS degrader. However, in mice bearing xenograft pancreatic tumours, orthotopic injection of the Vif-based degrader was The development of KRAS G12C inhibitors spurred several efforts to find new KRAS inhibitors, particularly those targeting KRAS G12D. , 2015) with a naphthol group at the 7-posi-tion on the quinazoline core was used as a parental compound (Ren et al. We devised a novel chemical knockdown strategy, CANDDY (Chemical Currently, five KRAS-G12D inhibitors are undergoing clinical trials, including the non-covalent inhibitor MRTX1133, the active-state inhibitor RMC-9805, and the Notably, BTX-10908 was significantly more potent than the clinical SOS1 inhibitor at reducing pERK levels and cell viability in multiple KRAS- and RTK-driven cell lines. The PROTAC Experts have developed a breakthrough small-molecule drug, a 'protein degrader'. By connecting various carbon chains, PEG chains, and tertiary amine linkers to the CRBN ligand pomalidomide, they ultimately developed the covalent degrader XY-4-88 (Fig. Based on these results, further studies are needed. Although it has been challenging to identify targeted therapies for cancers Our lead program, ASP3082, is the first protein degrader for mutated KRAS G12D to enter the clinic 1. ACBI3 is a selective and potent pan-KRAS degrader discovered via a structure-based design approach guided by optimization of VHL:PROTAC:KRAS ternary complex stability and durability 1,2. Here, we describe the preliminary safety and antitumor activity of ASP3082 mono-therapy in patients (pts) with previously treated advanced solid tumors. S. ASP3082, a The representative degrader XY-4-88 (4, Fig. There is also a KRAS-G12D degrader ASP3082 (Astellas), which binds KRAS-G12D to a E3 Ligase to degrade the protein and is currently in Phase 1 clinical trials (NCT05382559). 3 June 2024. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and The company also has an in-house candidate called ASP3082, a KRAS G12D degrader in phase 1 development for cancer. Although the approval of Sotorasib in 2021 by the FDA partially addressed the needs of patients with Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models. 0 International license perpetuity. Totally, 4. Moreover, tri-complex inhibitors RM-018 and RMC-6291, RAS degrader ASP3082, KRAS-targeted immunotherapies such as adoptive cell therapy, therapeutic cancer vaccine ELI-002, and antibody therapy have exhibited promising therapeutic prospects. There is going to be a lot of data coming out soon,” says Robert KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. These trials are in early dose-escalation stages, and no clinical combinations have been proposed yet. Nature Background: KRAS is one of the most frequently mutated oncogenes in various cancers. However, the moderate response rate and BTX-10908 is a first-in-class, oral degrader of SOS1, an important upstream target in the KRAS pathway. Revolution cited an overall response rate of 30% in second-line or later pancreatic cancer – an impressive result in this underserved disease, In 2023, the Zheng research group [57] developed a potent and selective KRAS(G12C) degrader, YN14 (Fig. opnMe is the open science portal of Boehringer Ingelheim. et al. Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Eur. opnMe® is the open science portal of Boehringer Ingelheim. Based on information gained by computational structure modelling, the authors develop a PROTAC that . Pan-cancer analysis identified that 19% of cases have PI3K/PTEN pathway mutation without RAS pathway mutation, suggesting that these cancer patients could benefit from AKT degrader therapy that leads to loss of AURKB. Structural and mechanistic features of degrader-mediated ternary complexes directly affect the pharmacological activity of degraders and thus represent an important SOS1 degradation resulted in the reduction of active KRAS, HRAS and MRAS levels when assayed by RAF-RBD pulldowns in MIA PaCa-2 (KRAS G12C) cells. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 Direct KRAS Degrader. Compound 3 still displayed positive cooperativity and long-lived ternary complex half-life (alpha = 17, K D = 340 nM by FP, K D = 80 nM and t 1/2 = Here the authors report the characterization of a CEACAM6-targeting antibody drug conjugate loaded with a BET protein degrader, showing antitumour activity in PDAC preclinical models. Notably, BI-2865 can Background: ASP3082 is a novel protein degrader selectively targeting KRAS G12D. Currently, a phase 1 clinical trial is The first reversible covalent degrader designed to target the KRAS G12C mutant protein, based on cyclopropionamide, has been reported. Specifically, compound 1 (Li et al. Here, we describe the development of novel SOS1 degraders and their activity in patient-derived CRC organoids (PDO). This workflow centers on the intracellular expression of a chimeric protein consisting of a high-affinity target-binding domain fused to an engineered E3 ligase adapter. KRAS mutations are one of the most common oncogenic drivers for multiple cancers. 27 February 2024. 122 In vivo experiments have been performed by injecting mutant KRAS H358 cancer cells stably expressing the RAS degraders into CD-1 Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. Our degrader series based on a novel warhead and a ligand that recruits VHL successfully engaged VHL in cells, bound KRAS G12D in vitro, induced VHL/KRAS G12D dimerization, and degraded KRAS G12D. On a molecular level, ASP3082 has a with the KRAS degrader while the pan-RAS degrader knocked. This molecule, called ACBI3, could potentially lead to new therapies independent of KRAS mutation type, improving Abstract. Targeting KRAS oncogenic mutants allows to clearly focus on the disease state Our lead program, ASP3082, is a novel protein degrader, originally discovered by Astellas, that targets mutated KRAS G12D, and is currently in Phase I clinical trials for the treatment of solid tumors. 2 degrader. Herein, we report the design, synthesis, and biological evaluation of a series of KRAS G12D PROTACs by connecting the The KRAS degrader induces regression of mutant KRAS H358 tumours. KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Currently, five KRAS-G12D inhibitors are undergoing clinical trials, including the non-covalent inhibitor MRTX1133, the active-state inhibitor RMC-9805, and the KRAS-G12D degrader ASP3082. The Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most mutated oncogene in human cancers. Herein, we report the development of the first-in-class endogenous KRASG12C degrader, LC-2, which combines MRTX849 with a VHL E3 ligase ligand39. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 Many patents are focused on overcoming this obstacle to achieve inhibition of KRAS G12D and other mutants. Astellas isn’t the only pharma that sees potential in protein degraders. 2 a, b). Here, taking advantage of our previous finding that Nedd4-1 is a KRAS mutations are the most prevalent oncogenic drivers in IMAs, with up to 86% of IMAs driven by KRAS compared with one-third of non-IMAs of the lung [64, 65]. KRAS gene mutation is widespread in tumors and plays an important role in various malignancies. The deal also includes the sale Named ASP3082, the investigational drug is the first degrader directed against G12D-mutant KRAS to enter human trials anywhere in the world. It harnesses innovation by linking the A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS. ; Yamanaka, Y. ASP3082, a first-in-class novel KRAS G12D degrader, exhibits remarkable anti-tumor activity in KRAS G12D-mutated cancer models. 212 reported a Vif-based bioPROTAC as their best KRAS degrader. Degrader resistant lines were associated with low AKT phosphorylation, wild type PI3K/PTEN status, and mutation of KRAS/BRAF. KRAS with druggable sites switch I/II and switch II with the best characterized inhibitors for these sites. It harnesses innovation by linking the best experts KRAS G12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Subsequently, LC-2, the first endogenous KRAS (G12C) degrader, was reported to rapidly engage and continuously degrade KRAS (G12C), which consisted of MRTX849 and the VHL E3 ligase ligand 136. Through opnMe, we now offer ACBI3, a first-in-class proteolysis targeting chimera (PROTAC), which arises from a successful collaboration with the University of Dundee (Centre for Targeted Protein Degradation, School of Life Sciences), and Abstract. All trials on the list are NCI-supported clinical trials, which are sponsored or otherwise financially supported by NCI. 091 µmol/L for H358 cells and 0. spotlight three focal points for sustained The development of mutations in protooncogene Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is known to be a driver of many common cancers, such as lung cancer, colorectal cancer, and Ahead of the Triple meeting, a big question whether Revolution Medicines’ KRAS G12D-selective inhibitor, RMC-9805, could buck the disappointing trend seen with this class of drugs – and the answer appears to be yes. Another attractive design of a protein degrader is Trim-Away, which takes advantage of the natural affinity of the E3 ubiquitin ligase TRIM21 to the Fc Named ASP3082, the investigational drug is the first degrader directed against G12D-mutant KRAS to enter human trials anywhere in the world. In 2013, the National Cancer Institute established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to create effective therapies for RAS-driven cancers. KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. OncologyPipeline reveals other KRAS G12D degrader projects at Arvinas, Risen Pharmaceuticals and Seed Therapeutics, but none has yet entered human trials. KRASG12X mutations are identified in AMG510, as the first approved inhibitor for KRAS G12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRAS G12C mutation. Editorial acknowledgement. A novel FEM1B covalent ligand called EN106 was also discovered, expanding the range of available ligands. 1 R&D Department, FuturedMe Inc. The application of KRAS inhibitors in the field of cancer treatment holds great promise. down all three K/N/HRAS proteins, in a dose dependent manner (Fig. 22 October 2023. Here, we designed a library of C12-directed covalent degrader In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a A First-Class Degrader Candidate Targeting Both KRAS G12D and G12V Mediated by CANDDY Technology Independent of Ubiquitination. This review uncovers their design strategies for KRAS G12D inhibitors. - Mechanism of Action & Protocol. RD0255359 is a highly potent and selective KRASG12C/D/V degrader with favorable PK properties that exhibits a promising therapeutic index in preclinical studies and can distribute into tumor tissue rapidly and abundantly after injection. Another KRAS G12D inhibitor, HRS-4642, forms a salt bridge with KRAS’s Asp12 . That is ASP3082, a novel protein degrader that targets mutated KRAS G12D and follows in the footsteps of Amgen’s KRAS inhibitor Lumakras (sotorasib), which became the first drug in the class to KRAS mutations are among the most frequent gain-of-function alterations found in patients with cancer and their therapeutic targeting has long been a key objective in precision oncology 8,9,10,11 Through drug design and optimization of the linker type, length, and flexibility, we developed a series of highly potent and selective KRAS G12C PROTACs. On a molecular level, ASP3082 has a dumbbell-like Direct blockade of KRAS driver mutations in colorectal cancer (CRC) has been challenging. After tumours reached 3–4 mm diameter, animals were separated into groups of 5 mice and treated or not with doxycycline (dox) in drinking a The time courses of the KRAS(G12C) and KRAS(WT) levels and the pERK level in RASless MEFs after the induction of the expression of the VHL–12VC1. ACBI3 suppresses oncogenic KRAS protein levels in Specifically, application of the GDP-state specific degrader uncovered the relative prevalence of the "off-state" of WT and various KRAS mutants in the cellular context. Targeting KRAS mutations is regarded as the “holy grail” of targeted cancer In a recent issue of Nature, Kim et al. We do not sell to patients. 045 µmol/L for PaCa-2 cells. Additionally, the activity HDCA1 degrader surpassed submicromolar levels during the same year. LC 2 induces selective degradation of KRAS G12C in These molecules engage KRASG12C and degrade an artificial GFP-KRASG12C fusion protein, but were unable to degrade endogenous KRAS. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent in However, their lead degrader XY-4-88 could not degrade endogenous KRAS G12C, as it appeared to directly ubiquitinate the GFP portion of the KRAS fusion protein. KRAS, HRAS and NRAS protein It’s fair to say that the KRAS G12D space has failed to live up to some companies’ hopes, with Jiangsu Hengrui’s inhibitor HRS-4642 disappointing at ESMO 2023, and Astellas’s degrader ASP3082 underwhelming at this RNK05047 is a first-in-class, small-molecule, tumor- and BRD4-selective protein degrader that was discovered and developed using Ranok’s proprietary approach to targeted protein degradation, CHAMP â. 4. , 2-3-11 Honcho, Nihonbashi, Chuo-ku, Tokyo 103-0023, Tokyo, Japan. ACBI3 achieves in vivo degradation of oncogenic KRAS. Merkel, PhD, of Oxford Direct blockade of KRAS driver mutations in colorectal cancer (CRC) has been challenging. [abstract]. Concept: ACBI3 is a proteolysis-targeting chimera that engages multiple oncogenic KRAS alleles with high affinity. It acts on the majority of KRAS mutants and inhibits proliferation in KRAS mutant cell lines covering a wide range of tumor types. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on Importantly, Boehringer Ingelheim plans to make the KRAS degrader compound ACBI3, freely available for the scientific community through its opnMe® portal, without any strings attached, which could catalyse future research on this important target. Although HRS-4642 exhibits similar binding affinity for both GDP-bound and GTP-bound KRAS G12D, crystallographic studies reveal the structural basis of inhibitor The ongoing study suggests that ASP3082, a novel KRAS G12D degrader, has an acceptable safety profile and promising antitumor activity, especially in pts with heavily pretreated PC. : 2938169-76-5. The KRAS crowd targets its next cancer mutations By Asher Mullard Clinic-ready inhibitors, degraders and molecular glues are pushing cancer frontiers by targeting KRAS variants including KRAS-G12D. AMG510, as the first approved inhibitor for KRAS G12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRAS G12C mutation. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). Here, we designed a library of C12-directed covalent degrader ESMO abstract data showed underwhelming results for Astellas’s first-in-class KRAS G12D degrader ASP3082, but the company is pressing on. We fully determined the optimal linker lengths and SOCS7-based KRAS degrader inhibits pancreatic cancer cells proliferation (A) Efficacy of SOCS7-based KRAS degrader to deplete its target in MIA PaCa-2 compared to a negative degrader (K19dm-SOCS7). TKD is composed of a We show that the KRAS degrader efficiently induces endogenous KRAS degradation in vitro and in vivo and specifically inhibits mutant KRAS tumours without affecting In this work, we provide preclinical validation for a single small-molecule degrader, targeting 13 of the 17 most prevalent KRAS mutants, that illuminates a new pan-KRAS degradation concept conferring potential for major clinical benefit. The compound could lead to new therapeutics and help scientists compare with noncovalent KRASG12D degraders based onKRASG12D-selectiveinhibitorscurrentlyun-dergoing early clinical testing (12). Inspired by these results, Crews et al. On the other hand, the pan-RAS degrader inhibited cell proliferation in a range of KRAS G12D is the most common KRAS mutation with an incidence rate of approximately 2. One of the primary causes of anticancer drug resistance is the frequently mutated RAS gene. ESMO 2023 – Revolution sets the bar in pan-KRAS inhibition. We fully determined the optimal linker lengths and Importantly, Boehringer Ingelheim plans to make the KRAS degrader compound ACBI3, freely available for the scientific community through its opnMe portal, without any strings attached, which could catalyse future research on this important target. NCI’s basic information about clinical trials explains the types and phases of trials and how they are carried out. ESMO 2023 – Pluvicto’s big splash gets an early preview. LC 2 is a mutant-selective KRAS Degrader (PROTAC ®), comprising a ligand for the von Hippel Lindau E3 ligase joined to the KRAS inhibitor MRTX849. 2020;11:3233. However, the efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid K-Ras mutations represent a most prevalent oncogenic alteration in human cancers. 1 In this review, we discuss the development of drugs targeting KRAS and KRAS signaling-related proteins, including small-molecule TPD-based chemicals, and their potential applications in In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. mutants with high prevalence in cancer patients. Pan-RAS protein degradation, however, affects proliferation irrespective of the RAS mutation. Many patents are focused on overcoming this obstacle to achieve inhibition of KRAS G12D and other mutants. The G-domain consists of p-loop, switch I Clinical data from lead pipeline assets: Phase 1 data from ASP3082, the first protein degrader targeting KRAS G12D mutant to enter clinical trials, in patients with advanced pancreatic, colorectal, and non-small cell lung cancer; and preclinical, translational/early clinical data from ASP1570, a novel DGKζ inhibitor, in patients with advanced KRAS mutation occurs in nearly 30% of human cancers, yet the most prevalent and oncogenic KRAS(G12D) variant still lacks inhibitors. 1q), by connecting AMG510 with the VHL ligand VH032 through a linker containing piperidine. The bromodomain transcription factor BRD4 is a key epigenetic regulator of oncogenes such as MYC and BCL2 and is involved in diverse cancer types. KRAS degrader-1 (compound 1) is a potent KRAS degrader. 1). Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. CC-BY 4. 1B). Finally, if delivery challenges can be addressed, anti-RAS biodegraders will be exciting candidates for clinical development. Degradation alone not enough? In the SERD (selective This degrader works by binding KRAS G12D to an E3 ligase, leading to the degradation of the protein. ACBI3 Chemical Structure. Other downstream signaling markers (pERK and pS6) were also decreased upon SOS1 degradation in KRAS G12C, G12V, G12S and G13D cell lines in 3D Western Blot assays. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. KRAS is an oncogene constitutively activated by mutations impeding GTP hydrolysis. This optimization Nagashima, T. CAS No. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. Nat Commun. Additionally, the KRAS G12D degrader ASP3082 is currently in Phase 1 clinical trials (NCT05382559). Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Clinical trials look at new ways Modalities and applications of targeted protein degradation (TPD) have rapidly expanded the therapeutic possibilities of proximity induced pharmacology. 5 times higher than the G12C mutation, Yoshinari, T. KRAS is the most frequently mutated oncogene in human cancers, but to date, only KRASG12C inhibitors have been FDA-approved. “We will see more and more Kirsten rat sarcoma (KRAS) has historically been considered an “undruggable” target due to its lack of deep “pockets” and is associated with poor prognosis and resistance to standards of care in several tumor types. KRAS degrader-1 target specific proteins for degradation through the autophagy-lysosomal degradation pathway. These data show that specific KRAS Design of a KRASG12C Degrader Library We based the design of our KRAS G12Cdegrader library on a G12C-directed covalent quinazoline-based switch II pocket ligand as the target recruiting warhead (Table 1). 2 Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, To gain insights into the advantages and feasibility of KRAS targeted degradation, we applied a protein-based degrader (biodegrader) approach. This degrader works by binding KRAS G12D to an E3 ligase, leading to the degradation of the protein. Currently, at least nine KRAS G12D-selective inhibitors are under clinical evaluation KRAS G12D inhibition has so far failed to live up to the hype, and this seems unlikely to change any time soon. By employing an MCB-294 derivative as the KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system As further proof of potential, he points to a recent preprint that identified a KRAS degrader that acts by gluing the oncogene to its native E3 ligase Nedd-1. KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. Revolution pushes home its pan-KRAS advantage. KRAS is the most frequently mutated cancer-causing oncogene and is mutated in over 20% of all human cancers, including an (A) Efficacy of SOCS7-based KRAS degrader to deplete its target in MIA PaCa-2 compared to a negative degrader (K19dm-SOCS7). J. Etsuko Miyamoto-Sato. In particular, considerable efforts have been made to treat KRAS-induced cancers by directly and indirectly controlling the ac Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1–Akt blockade and potent tumor suppression alone or combined KRAS G12C mutant using this approach22,23. 1) only showed the degradation in GFP-KRAS G12C reporter cells, but could not degrade endogenous KRAS G12C in pancreatic and lung cancer cells. The group is now dosing higher in the hope that this might lead to more KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Crew's group disclosed an endogenous KRAS G12C degrader LC-2 (5, Fig. , 2-3-11 Honcho, Nihonbashi, Chuo-ku, KRAS degrader specifically depletes KRAS in cancer cells. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRAS G12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). RAS oncogene mutations are prevalent in approximately 19% of cancer patients, with the most frequent alteration occurring in codon 12 of the KRAS gene, resulting in a variety of G12X oncoproteins. KRAS is composed of two splice variants KRAS4A and KRAS4B, among which KRAS4B is the major isoform. This workflow Applying the concept of TPD we have discovered ASP3082, a first-in-class and selective KRAS G12D degrader. NCT05382559. Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models (AACR 2023) ASP3082 is a potential therapeutic agent for patients with tumors harboring the KRAS G12D mutation. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. After the successful use of a small-molecule inhibitor against KRAS G12C, a hetero-bifunctional molecule was explored to test PROTAC-mediated mutant KRAS degradation . Phase I clinical trials are underway in the U. Herein, we designed a series of potent inhibitors that can form KRAS is an important oncogenic driver which is mutated in numerous cancers. However, there is no direct KRAS ACBI3 (compound 7) is a pan-KRAS degrader. The design of these degraders as Importantly, Boehringer Ingelheim plans to make the KRAS degrader compound ACBI3, freely available for the scientific community through its opnMe portal, without any strings attached, which could catalyse future research on this important target. Interestingly, although the KRAS-specific degrader eliminated both wildtype and mutant KRAS, cell proliferation was only inhibited in the context of KRAS-mutant cancer cell lines, highlighting that degradation and phenotypic outcomes are not always correlated. Abstract. Annals of In our study, PROTACs targeting mutant KRAS G12D have been designed and developed. In this work, we provide preclinical vali-dation for a single small-molecule degrader, targeting 13 of the 17 most prevalent KRAS mutants, that illuminates a new pan-KRAS degradation concept conferring potential for Degrader takes out many forms of KRas Molecule sends 13 of the 17 most common forms of this cancer-related protein to the cell’s garbage-disposal system by Although the DARPin K19 does not specifically target mutant KRAS, cell proliferation is inhibited only in mutant KRAS cancer cells and the DARPin degrader has no effect on cells with wild-type KRAS or mutant NRAS or HRAS. ASCO 2024 – AstraZeneca’s GPC3 secret sauce. In our study, PROTACs targeting mutant KRAS G12D have been designed and developed. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer The clinical trials on this list are studying kras g12d degrader asp3082. It is LC-2 covalently binds KRAS G12C with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRAS G12C degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRAS G12C cell lines. Medical writing support was provided by Steven F. 1) with the MRTX849 linkage VHL ligand [22, 23]. We fully determined the optimal linker lengths and Subsequently, LC-2, the first endogenous KRAS (G12C) degrader, was reported to rapidly engage and continuously degrade KRAS (G12C), which consisted of MRTX849 and the VHL E3 ligase ligand 136. Drug resistance continues to be a major problem associated with cancer treatment. Here, Krone et al. Editorial acknowledgement The function and significance of RAS proteins in cancer have been widely studied for decades. Our data revealed that TKD selectively binds to KRAS in cancer cells establish compound 4 as a highly selective KRAS degrader acting on a broad spectrum of KRAS . YN14 exhibited growth inhibition with IC50 values of 0. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the with more than 25 degrader drugs currently in clinical trials for several indications ( 7, 8). 17 October 2023. Impact: This study provides preclinical proof of concept for the antitumor efficacy of pan-KRAS degradation. , 2014). Cancer 174, S30 (2022). chimera) degrader platform • Elimination of disease -causing proteins, instead of inhibition • Power of genetic medicines with KRAS, Myc) and more validated targets • Clinical proof- of-concept from two programs: ARV -110 and ARV -471 • ARV-110, our androgen receptor PROTAC, has shown safety, efficacy signal, KRAS, a critical gene involved in cellular processes, can initiate tumor formation when mutated. First-in-human data with Astellas’s G12D degrader ASP3082, released this week in an ESMO abstract, look lacklustre, raising questions about whether a degrader approach is any better than inhibition. 30 September 2024. Degrader YN14 significantly inhibited KRAS G12C-mutant cancer cell growth and induced potent KRAS G12C degradation in vivo and in vitro. MLN4924 (1 µM) or MG132 (5 µM Importantly, Boehringer Ingelheim plans to make the KRAS degrader compound ACBI3, freely available for the scientific community through its opnMe portal, without any strings attached, which could KRAS is an important and validated target in LUAD, PDAC, and CRC in which it actively participates in tumor initiation and maintenance. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as Interestingly, Pan et al. “There are three differ-ent modalities coming online contemporane - ously. F a degrader and molecular glues. We observe rapid degradation through a bona fide PROTAC mechanism in both To gain insights into the advantages and feasibility of KRAS targeted degradation, we applied a protein-based degrader (biodegrader) approach. The ongoing study suggests that ASP3082, a novel KRAS G12D degrader, has an acceptable safety profile and promising antitumor activity, especially in pts with heavily pretreated PC. select article 59 (PB049) - PIN-A1, a novel Casein Kinase 1α-selective molecular glue degrader, demonstrates strong antitumor activity via activation of the p53 pathway in preclinical models of AML with a favorable safety profile a First-in-class novel KRAS G12D degrader, exhibits remarkable anti-tumor activity in KRAS G12D mutated cancer Having established compound 2 as a VHL-based KRAS degrader, we went on to synthesize a molecular matched pair, replacing the oxygen atom in the linker by a methylene group yielding compound 3 (Fig. No effect was observed with the control degraders This study developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants and reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers. KRAS proteins consist of G-domain, the membrane-targeting domain and C-terminal hypervariable region (Fig. hfbv xao czwqhb onnw pwe vbuxx fbjs pyqfcd iaza iwwuab