CoChat
Sign Up
Cited by 34Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

Abstract 3596: RM-036, a first-in-class, orally-bioavailable, Tri-Complex covalent KRASG12D(ON) inhibitor, drives profound anti-tumor activity in KRASG12D mutant tumor models

Knox, John E., Jiang, Jingjing, Burnett, G. Leslie, Liu, Yang, Weller, Caroline E., Wang, Zhican, McDowell, Laura, Steele, Shelby L. +9 more·2022·Cancer Research
DOI 10.1158/1538-7445.am2022-3596
Open this paper in CoChat — free account

Abstract

KRASG12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US. The KRASG12D mutation occurs commonly in multiple tumor histotypes, including about 20%, 29% and 17% of KRAS mutant colorectal, pancreatic, and non-small cell lung cancers, respectively. However, there are no directly targeted inhibitors of KRASG12D in clinical development. Mutant RAS proteins exist predominantly in the GTP-bound RAS(ON) state, leading to excessive downstream signaling via interaction with effectors such as RAF kinases. Highly selective inhibitors that covalently target the KRASG12C(OFF) state and inhibit conversion to KRASG12C(ON) have been shown to be active and well tolerated in the clinic, and we have described a novel, covalent tri-complex KRASG12C(ON) inhibitor that has robust anti-tumor activity and is well tolerated in preclinical studies. Developing a covalent inhibitor of KRASG12D presents several challenges. The Asp residue in KRASG12D is significantly less reactive toward electrophiles than is Cys. And most reported covalent chemical warheads capable of reacting with Asp exhibit high nonspecific reactivity. The intrinsic GTP hydrolysis rate of KRASG12D is about 2.6-fold lower than that of KRASG12C, further biasing the cellular KRASG12D pool to the RAS(ON) state and emphasizing the importance of targeting the KRASG12D(ON) state for maximal suppression of this oncogenic driver. Based on these considerations we designed RM-036, a potent, selective, orally bioavailable, covalent KRASG12D(ON) inhibitor with attractive drug-like properties. It forms a tri-complex between the abundant intracellular chaperone cyclophilin A (CypA) and the active state of KRASG12D, positioning the warhead relative to KRASG12D and enabling selective covalent engagement of Asp. In cellular models, RM-036 exhibited efficient and selective covalent binding to KRASG12D, with no detectable reactivity toward the adjacent Asp residue in cells with the KRASG13D mutation. RM-036 showed low off-target reactivity in cell-based proteomic screens. RM-036 potently inhibited growth and induced apoptosis in KRASG12D mutant cancer cells in vitro but not in BRAFV600E-dependent cells. RM-036, as a single agent, produced deep, durable, and dose-dependent suppression of tumor RAS pathway activation with covalent target engagement in vivo following repeat oral administration. Profound tumor regressions, including complete regressions, were observed in various KRASG12D mutant xenograft models upon treatment with RM-036. All treatments regimens tested with RM-036 were well tolerated in vivo. These preclinical findings provide a strong foundation for advancing RM-036 toward clinical evaluation in patients with tumors bearing the KRASG12D mutation. Citation Format: John E. Knox, Jingjing Jiang, G. Leslie Burnett, Yang Liu, Caroline E. Weller, Zhican Wang, Laura McDowell, Shelby L. Steele, Shook Chin, Kang Jye Chou, Fang Wang, Mengqi Zhong, Elena S. Koltun, David Wildes, Mallika Singh, Adrian L. Gill, Jacqueline A. Smith. RM-036, a first-in-class, orally-bioavailable, Tri-Complex covalent KRASG12D(ON) inhibitor, drives profound anti-tumor activity in KRASG12D mutant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3596.

Integrity signals

Registry

Crossref · 10.1158/1538-7445.am2022-3596

Cites

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Still being checked.

Cited by

Sorted by citations

Related

Authors
Knox, J. E., Jiang, J., Burnett, G. L., Liu, Y., Weller, C. E., Wang, Z., McDowell, L., Steele, S. L., Chin, S., Chou, K. J., Wang, F., Zhong, M., Koltun, E. S., Wildes, D., Singh, M., Gill, A. L., & Smith, J. A.
Affiliations
Revolution Medicines (United States) (US)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2022-06-15
Volume
82
Issue
12_Supplement
Pages
3596-3596
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/1538-7445.am2022-3596
OpenAlex
W4282962236
Cited by
34
References
0
Citations by year
2026: 4 · 2025: 6 · 2024: 11 · 2023: 11 · 2022: 2
Type
conference abstract
Language
en
Open access
closed
Locations
Cancer Research (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
KRAS G12D, covalent KRAS inhibitor, cyclophilin A, oral bioavailability, KRAS-mutant cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, anticancer activity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review