molecules of the month


selective rev. DNA methyltransferase inhibitor

preclinical eff. at 30 mpk SC BID (xenograft)

from 1.8M cmpd enzymatic HTS + opt.

Nature Cancer


Chemical structure of molecule GSK3685032
1 min read

The GSK DNMT1 inhibitor GSK3685032 is a first-in-class, non-nucleoside, reversible and selective inhibitor of the epigenetic target DNA-methyltransferase 1 (DNMT1). Commonly prescribed hypomethylating agents (HMAs) such as decitabine are incorporated into DNA and inhibit DNMT1, DNMT3A, and DNMT3B irreversibly, and as a consequence are toxic to normal blood cells. GSK3865032 competes reversibly with the active-site loop of DNMT1 (PDB:6X9K) for penetration into hemi-methylated DNA, and induces robust loss of DNA methylation without affecting DNMT3A or DNMT3B. Due to improved in vivo tolerability over hypomethylating agents, GSK3685032 demonstrates superior tumor regression and survival in AML models to decitabine. Thanks to the improved therapeutic index, it may be potentially viable in solid tumors where HMAs have not been very successful. This molecule will be…

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