| Structural highlights
Function
PMYT1_HUMAN Acts as a negative regulator of entry into mitosis (G2 to M transition) by phosphorylation of the CDK1 kinase specifically when CDK1 is complexed to cyclins. Mediates phosphorylation of CDK1 predominantly on 'Thr-14'. Also involved in Golgi fragmentation. May be involved in phosphorylation of CDK1 on 'Tyr-15' to a lesser degree, however tyrosine kinase activity is unclear and may be indirect. May be a downstream target of Notch signaling pathway during eye development.[1] [2]
Publication Abstract from PubMed
PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.
Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.,Szychowski J, Papp R, Dietrich E, Liu B, Vallee F, Leclaire ME, Fourtounis J, Martino G, Perryman AL, Pau V, Yin SY, Mader P, Roulston A, Truchon JF, Marshall CG, Diallo M, Duffy NM, Stocco R, Godbout C, Bonneau-Fortin A, Kryczka R, Bhaskaran V, Mao D, Orlicky S, Beaulieu P, Turcotte P, Kurinov I, Sicheri F, Mamane Y, Gallant M, Black WC J Med Chem. 2022 Jul 26. doi: 10.1021/acs.jmedchem.2c00552. PMID:35880755[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu F, Stanton JJ, Wu Z, Piwnica-Worms H. The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Mol Cell Biol. 1997 Feb;17(2):571-83. PMID:9001210
- ↑ Liu F, Rothblum-Oviatt C, Ryan CE, Piwnica-Worms H. Overproduction of human Myt1 kinase induces a G2 cell cycle delay by interfering with the intracellular trafficking of Cdc2-cyclin B1 complexes. Mol Cell Biol. 1999 Jul;19(7):5113-23. PMID:10373560
- ↑ Szychowski J, Papp R, Dietrich E, Liu B, Vallee F, Leclaire ME, Fourtounis J, Martino G, Perryman AL, Pau V, Yin SY, Mader P, Roulston A, Truchon JF, Marshall CG, Diallo M, Duffy NM, Stocco R, Godbout C, Bonneau-Fortin A, Kryczka R, Bhaskaran V, Mao D, Orlicky S, Beaulieu P, Turcotte P, Kurinov I, Sicheri F, Mamane Y, Gallant M, Black WC. Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306. J Med Chem. 2022 Jul 26. doi: 10.1021/acs.jmedchem.2c00552. PMID:35880755 doi:http://dx.doi.org/10.1021/acs.jmedchem.2c00552
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