Astellas joins in clinical development of covalent KRAS inhibitors

On November 4, Dana-Farber Cancer Institute and Astellas Pharma announced a three-year collaboration to research and develop small molecule covalent KRAS inhibitors for the treatment of cancers.

KRAS is a oncogenic GTPase involving in many signal transduction pathways. About 97.7% of pancreatic ductal adenocarcinoma, 44.7% of colorectal adenocarcinoma, 30.9% of lung adenocarcinoma, 22.8 % of multiple myeloma, and 21.4% of uterine corpus endometrioid carcinoma harbor activating KRAS mutations[1].

Howerver, KRAS is a well-known undruggable target. Small molecules targeting the guanine nucleotide binding site of KARS is difficult because both GTP and GDP bind to Ras with sub-nanomolar affinity and their intracellular concentrations are very high. Worse, there is no known allosteric regulatory site that would allow tight binding of small molecules. Despite more than three decades of effort by academia and industry, no effective RAS inhibitor has been approved.

KRAS G12C is a common activating mutation present in roughly 50 % of Ras-driven lung adenocarcinomas. This mutation places a cysteine adjacent to the active site, providing a covalent approach targeting KRAS. Covalent inhibitor could overcome the problem of high competing GTP/GDP.

SML-8-73-1[2] is a GDP analogue which contains an electrophilic chloroacetamide attached to the beta phosphate, that can covalently modify Cys12 of KRAS mutant. SML-10-70-1, a prodrug of SML-8-73-1, inhibits lung cancer A549, H23, and H358 cells with an EC50 of 43.8 μM, 47.6 μM, and 26.6 μM.

In November 2013, a non-nucleoside covalent KRAS inhibitor was reported in Nature[3]. This compound inhibits lung cancer H1792 cells with an EC50 of 0.32 μM. Considering the low-affinity of SML-8-73-1, continued chemical optimization could be warranted before clinical test.

[1] Nat Rev Drug Discov. 2014, 13(11), 828-851.

[2] Angew Chem Int Ed.2014, 53, 199-204.

[3] Nature. 2013, 503(7477), 548-551.


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