Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

Table8 RP6306 disco

This med chem paper is an excellent write up of a candidate drug discovery, starting with the screening hit. It is remarkable, as a small deck of 560 kinase inhibitors were screened at the start, and this only yielded a couple of hits. One of these was the phenol compound with a tricyclic core. Phenols are problematic on the one hand the weakly acidic group can form two hydrogen bonds or an electrostatic interaction but usually suffer from high secondary metabolism. Optimisation of the phenol ring yielded atropisomers that exhibited good stability and a further sweep of SAR improved matters further with increased selectivity. The tri-cyclic central ring was replaced successfully with a bicycle, which improved physical properties. The paper includes comprehensive synthesis and in-vivo xenograph profiling. We noted that one phenol replacement tried looked like are good compound too (benzopyrazole) – we are expecting another paper working from this start point. Non-the-less an excellent write up.

J. Med. Chem. 2022, 65, 15, 10251–10284