Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors
This month’s paper is an excellent piece of work from our friends at Genentech. It is noteworthy and commendable of the authors to publish this work, as the project did not produce a candidate drug. The authors describe the compounds and SAR to aid future drug design if VPS34 is found as an anti-target, as the research found that inhibition of VPS34 produced toxic effects in animal models. Thus the target is not applicable for oncology treatments and must be treated as a safety concern. Non-the-less the paper is well written and the work well described. Selected screening of known PI3kinase inhibitors yielded several start points and these were optimised using structure based design. A tightly bound water was key to inhibition. There is some excellent creativity and use of chiral alkyl groups (what is the shape of compound 26 I wonder) to optimise the profile. These too might be inspiring.
Dennis X. Hu*, et al