RMC-9805
[CAS# 2922732-54-3]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: RMC-9805
• Synonyms: KRAS G12D inhibitor 18; (2S)-2-cyclopentyl-2-[(5S)-2-[(2R,3R)-3-cyclopropyl-1-methylaziridine-2-carbonyl]-2,7-diazaspiro[4.4]nonan-7-yl]-N-[(6S,8S,14S)-21-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]acetamide
• Molecular Formula: C₆₃H₈₈F₃N₁₁O₇
• Molecular Weight: 1168.44
• CAS Registry Number: 2922732-54-3
• SMILES: C[C@@H](C1=C(C=C(C=N1)N2CCN(CC2)C3CC3)C4=C5CC(COC(=O)[C@@H]6CCCN(N6)C(=O)[C@H](C[C@H]7CN(CCO7)C8=CC5=C(N4CC(F)(F)F)C=C8)NC(=O)[C@H](C9CCCC9)N1CC[C@@]2(C1)CCN(C2)C(=O)[C@H]1[C@H](N1C)C1CC1)(C)C)OC

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Index of refraction: 1.697 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Danger
• Hazard Statements: H302-H318-H410
• Precautionary Statements: P273-P280-P301+P312+P330-P305+P351+P338+P310
• Transport Information: UN 3077

Discovory and Applicatios

RMC-9805 is a small-molecule therapeutic agent developed as a selective inhibitor of KRAS G12D, a common and oncogenic mutation in the KRAS gene. The KRAS gene encodes a small GTPase protein that plays a critical role in cell signaling pathways regulating proliferation, differentiation, and survival. Mutations at codon 12 of KRAS, such as the substitution of glycine with aspartic acid (G12D), result in constitutive activation of the KRAS protein, leading to uncontrolled cellular growth and the development of various types of cancer, most notably pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

The development of RMC-9805 by Revolution Medicines follows years of research focused on directly targeting KRAS mutations, a historically challenging task due to the protein’s high affinity for GTP/GDP and lack of suitable binding pockets. RMC-9805 belongs to a class of compounds known as RAS(ON) inhibitors. Unlike earlier strategies that attempted to inhibit KRAS in its inactive GDP-bound form, RMC-9805 is designed to bind selectively to the active, GTP-bound conformation of KRAS G12D. This mechanism allows the compound to inhibit signaling activity specifically in cancer cells harboring the mutation without affecting normal cells expressing wild-type KRAS.

The design of RMC-9805 incorporates a covalent binding strategy, enabling it to form a stable, irreversible bond with the mutant residue at position 12 in the GTP-bound KRAS G12D protein. This targeted interaction contributes to the molecule’s high specificity and potency. Preclinical studies in xenograft models of KRAS G12D-mutant tumors demonstrated that RMC-9805 induces significant tumor regression, validating its biological activity and therapeutic potential. These results prompted the initiation of clinical trials to assess its safety, tolerability, pharmacokinetics, and antitumor efficacy in humans.

The compound entered clinical development as part of a broader effort to address unmet medical needs in patients with KRAS G12D-mutant cancers. RMC-9805 is currently being evaluated in a first-in-human Phase 1/1b clinical trial, enrolling patients with advanced solid tumors that harbor the KRAS G12D mutation. The trial is structured to include dose escalation and expansion cohorts to identify the recommended dose for further clinical investigation and to explore preliminary efficacy signals. Patient populations include individuals with pancreatic, colorectal, and lung cancers that have progressed on prior lines of therapy.

One of the primary therapeutic applications of RMC-9805 is in pancreatic ductal adenocarcinoma, where KRAS mutations are found in over 90% of cases and G12D is the most prevalent substitution. The prognosis for this disease remains poor due to late diagnosis and limited treatment options. RMC-9805 offers a potential new avenue for treatment by directly targeting the mutant driver of oncogenesis in this cancer. Similarly, the compound is being studied in non-small cell lung cancer and colorectal cancer, where KRAS G12D mutations are also found, albeit at lower frequencies compared to pancreatic cancer.

In early clinical observations, RMC-9805 has shown signs of tumor regression and disease control in patients with advanced, previously treated cancers. The safety profile has been consistent with expectations for targeted therapies, with manageable side effects that include gastrointestinal symptoms and skin-related adverse events. These findings support continued clinical development and suggest that RMC-9805 could become an important component of precision oncology strategies aimed at KRAS-mutant cancers.

By selectively inhibiting KRAS G12D in its active state, RMC-9805 represents a significant advancement in the direct targeting of oncogenic RAS proteins. Its development reflects the ongoing innovation in drug discovery aimed at addressing previously undruggable targets and expanding therapeutic options for patients with genetically defined malignancies. The continued evaluation of RMC-9805 in clinical trials will determine its role in future cancer treatment protocols and its potential to improve outcomes for patients with aggressive and treatment-resistant tumors.