Director - DMPK Repare Therapeutics Saint-Laurent, Quebec, Canada
PKMYT1 inhibition is a promising therapeutic target for the treatment of certain types of DNA damage response cancers with CCNE1 amplification. A drug discovery campaign was initiated to find a first in class, selective inhibitor to investigate the pharmacological role of PKMYT1. A tricyclic phenolic lead was identified and potency optimization through phenol ring modification led to the formation of stable atropisomer mixtures. Due to vastly different potency and ADME properties, each atropisomer was isolated by chiral SFC for further profiling. The initial tricyclic series, while potent, suffered from poor solubility / absorption but early formulation intervention allowed for a rapid in vivo go-no-go decision. ADME properties were improved by truncation of tricyclic leads to become more drug-like. As a novel target, our understanding of in vivo PK-PD relationships benefited from formulations developed to produce different pharmacokinetic profiles in the mouse. RP-6306 successfully demonstrated on-target PKMYT1 inhibition of 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.
Learning Objectives:
Describe the hurdles in transitioning a novel small molecule from lead ID to the clinic.
Develop strategies to overcome multidisciplinary challenges faced during lead optimization and candidate selection.
Appreciate the use of different formulation modalities to accelerate early drug discovery
