Synonyms: (Rac)-RP-6306
Compound class:
Synthetic organic
Comment: Lunresertib (RP-6306) is the first lead candidate in the class of protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) inhibitors to be advanced for clinical evaluation [3]. It is orally bioavailable and selective for PKMYT1, and it is active in appropriate preclinical xenograft models of solid tumours [1]. PKMYT1 is a negative regulator of CDK1 [2], and its inhibition induces activation of CDK1 selectively in CCNE1-overexpressing cells; CCNE1 being a chromosome 19q12 locus that is amplified in multiple tumour types and which is a marker of poor prognosis and/or insensitivity to cytotoxic oncotherapies. As a monotherapy lunresertib induces synthetic lethality in combination with CCNE1 amplification (or alongside inactivating mutations in FBXW7 and PPP2R1A).
Structure note: the INN record for lunresertib does not specify the (S) stereo specification that is declared in the original disclosure of RP-6306's chemical structure [3]. We depict the racaemic mixture with no defined stereo centers. |
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Bioactivity Comments |
RP-6306 displays PKMYT1 selectivity (29-4000-fold) over five ephrins (A1, A2, B2, B3, and B4), FRK, cSRC, and the related WEE1 kinase in the NanoBRET cell-based target engagement assay [3]. |