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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References |
1. Gallo D, Young JTF, Fourtounis J, Martino G, Álvarez-Quilón A, Bernier C, Duffy NM, Papp R, Roulston A, Stocco R et al.. (2022)
CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature, 604 (7907): 749-756. [PMID:35444283] |
2. Lee MH, Yang HY. (2001)
Negative regulators of cyclin-dependent kinases and their roles in cancers. Cell Mol Life Sci, 58 (12-13): 1907-22. [PMID:11766887] |
3. Szychowski J, Papp R, Dietrich E, Liu B, Vallée F, Leclaire ME, Fourtounis J, Martino G, Perryman AL, Pau V et al.. (2022)
Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306. J Med Chem, 65 (15): 10251-10284. [PMID:35880755] |