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

  • J Med Chem. 2023 Oct 26;66(20):14278-14302. doi: 10.1021/acs.jmedchem.3c01319.
Murat Kücükdisli  1 ,  Hassen Bel-Abed  1 ,  Davide Cirillo  1 ,  Wen-Ting Lo  1 ,  Nina-Louisa Efrém  1 ,  André Horatscheck  1 ,  Liudmila Perepelittchenko  1 ,  Polina Prokofeva  2 ,  Theresa A L Ehret  3  4 ,  Silke Radetzki  1 ,  Martin Neuenschwander  1 ,  Edgar Specker  1 ,  Guillaume Médard  2 ,  Susanne Müller  3  4 ,  Stephanie Wilhelm  2 ,  Bernhard Kuster  2 ,  Jens Peter von Kries  1 ,  Volker Haucke  1 ,  Marc Nazaré  1
Affiliations
  • 1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, 13125 Berlin, Germany.
  • 2. Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
  • 3. Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 4. Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
PMID: 37819647 DOI: 10.1021/acs.jmedchem.3c01319
Abstract

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.

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