Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306
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Published on: January 22, 2019
Janek Szychowski1, Robert Papp1, Evelyne Dietrich1
1Repare Therapeutics, Inc., 7210 Frederick-Banting, Ville St-Laurent, QC H4S 2A1, Canada.
Abstract:
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.
Insights
Researchers developed RP-6306, a potent and selective PKMYT1 inhibitor, to target cancers with CCNE1 amplification. This first-in-class drug candidate shows promise in preclinical models and is now in Phase 1 clinical trials.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Protein kinase mutated intolyl 1 (PKMYT1) regulates CDK1 phosphorylation, presenting a therapeutic target in DNA damage response cancers.
- A synthetic lethal relationship exists between PKMYT1 and CCNE1 amplification, a common event in various solid tumors.
Purpose of the Study:
- To develop selective PKMYT1 inhibitors for therapeutic intervention.
- To investigate the pharmacological role of PKMYT1 in cancer treatment.
Main Methods:
- Structure-based drug design was employed to optimize PKMYT1 inhibitors.
- Atropisomers of dimethylphenol analogs were separated and profiled as single enantiomers.
- ADME properties were optimized to identify potent and selective drug candidates.
Main Results:
- Compound 1 was identified as an initial weak PKMYT1 inhibitor, with potency enhanced by dimethylphenol introduction.
- Potent and selective PKMYT1 inhibitors were successfully developed, including the clinical candidate RP-6306.
- RP-6306 demonstrated inhibition of CCNE1-amplified tumor cell growth in preclinical xenograft models.
Conclusions:
- RP-6306 is a first-in-class PKMYT1 inhibitor with demonstrated efficacy in preclinical models of CCNE1-amplified cancers.
- RP-6306 is currently undergoing Phase 1 clinical trials for the treatment of various solid tumors, highlighting its therapeutic potential.
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