Covalent Guanosine Mimetic Inhibitors of G12C KRAS
Open accessAbstract
Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure–activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.
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XY-02-075 is expected to be a promising compound despite a 40-fold reduction in affinity compared to SML-8-73-1.
“XY-02-075 is expected to be a promising compound despite 40 folds reduction in affinity compared to SML-8-73-1.92”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [92]
The chemical and enzymatic stability of XY-02-075 is greatly improved by methylene substitution of the central oxygen in the phosphonic anhydride bonds of SML-8-73-1 and SM-10-70-1.
“The chemical and enzymatic stability of XY-02-075 is greatly improved by methylene substitution of the central oxygen in the phosphonic anhydride bonds of SML-8-73-1 and SM-10-70-1.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [92]
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Self-citation
- Authors
- Xiong, Y., Lu, J., Hunter, J., Li, L., Scott, D., Choi, H. G., Lim, S. M., Manandhar, A., Gondi, S., Sim, T., Westover, K. D., & Gray, N. S.
- Affiliations
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Daegu-Gyeongbuk Medical Innovation Foundation (KR)
- Korea Institute of Science and Technology (KR)
- Korea University (KR)
- Corresponding author
- Westover, Kenneth D.
- Gray, Nathanael S.
- ORCID
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-12-15
- Volume
- 8
- Issue
- 1
- Pages
- 61-66
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC5238463
- OpenAlex
- W2557331116
- Cited by
- 66
- References
- 42
- Citations by year
- 2025: 6 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 13 · 2019: 14 · 2018: 9 · 2017: 6
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation (I1829)
- Astellas Pharma
- U.S. Department of Defense (W81XWH-16-1-0106)
- V Foundation for Cancer Research
- 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 › Protein Tyrosine Phosphatases
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- covalent inhibitors, structure-activity relationship, hydrolytic stability, prodrugs, Ras GTPase, crystal structure
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