Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition

Murat Kücükdisli, Hassen Bel-Abed, Davide Cirillo, Wen Ting Lo, Nina Louisa Efrém, André Horatscheck, Liudmila Perepelittchenko, Polina Prokofeva, Theresa A.L. Ehret, Silke Radetzki, Martin Neuenschwander, Edgar Specker, Guillaume Médard, Susanne Müller, Stephanie Wilhelm, Bernhard Kuster, Jens Peter Von Kries, Volker Haucke, Marc Nazaré

Research output: Contribution to journalArticlepeer-review


Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure-activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more than 118 diverse kinases showed no off-target kinase inhibition. Notably, by addressing a selectivity pocket, PITCOIN4 showed nanomolar inhibition of PI3K-C2α and >100-fold selectivity in a general kinase panel. Our study paves the way for the development of novel therapies for diseases related to PI3K-C2α function.

Original languageEnglish
Pages (from-to)14278-14302
Number of pages25
JournalJournal of Medicinal Chemistry
Issue number20
StatePublished - 26 Oct 2023


Dive into the research topics of 'Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition'. Together they form a unique fingerprint.

Cite this