molecules of the month

“Compound 25,” inhibits HPK1 via a rare “P-loop folded” active site conformation. The molecule was nominated by reviewer Julien Lefranc, and structural biologist Yoana Dimitrova shares some insight here: “The ‘folded P-loop’ conformation is considered “extremely unusual” – authors of a 2011 paper looked into this and found it in only 62 out of 2690 complexes for 7 different kinase targets out of 56 covered in the database, an incidence of 12.5%. What is important is that the folded P-loop is found in structures of kinase + compound, so we just may not have found compounds that lead to the folded conformation for the other kinases.” The P-loop folded conformation may present additional ways to address selectivity in kinase programs.…