Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A

  • J Med Chem. 2021 Nov 11;64(21):15883-15911. doi: 10.1021/acs.jmedchem.1c01245.
Lars Wortmann  1 ,  Nico Bräuer  1 ,  Simon J Holton  1 ,  Horst Irlbacher  1 ,  Jörg Weiske  1 ,  Christian Lechner  1 ,  Robin Meier  1 ,  Jakob Karén  2 ,  Catrine Berthold Siöberg  2 ,  Vera Pütter  1 ,  Clara D Christ  1 ,  Antonius Ter Laak  1 ,  Philip Lienau  1 ,  Ralf Lesche  1 ,  Barbara Nicke  1 ,  Shing-Hu Cheung  1 ,  Marcus Bauser  1 ,  Andrea Haegebarth  1 ,  Franz von Nussbaum  1 ,  Dominik Mumberg  1 ,  Clara Lemos  1
Affiliations
  • 1. Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
  • 2. Pelago Bioscience AB, Banvaktsvägen 20, 171 48 Solna, Sweden.
PMID: 34699202 DOI: 10.1021/acs.jmedchem.1c01245
Abstract

PIP4K2A is an insufficiently studied type II lipid kinase that catalyzes the conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P2). The involvement of PIP4K2A/B in Cancer has been suggested, particularly in the context of p53 mutant/null tumors. PIP4K2A/B depletion has been shown to induce tumor growth inhibition, possibly due to hyperactivation of Akt and reactive oxygen species-mediated Apoptosis. Herein, we report the identification of the novel potent and highly selective inhibitors BAY-091 and BAY-297 of the kinase PIP4K2A by high-throughput screening and subsequent structure-based optimization. Cellular target engagement of BAY-091 and BAY-297 was demonstrated using cellular thermal shift assay technology. However, inhibition of PIP4K2A with BAY-091 or BAY-297 did not translate into the hypothesized mode of action and antiproliferative activity in p53-deficient tumor cells. Therefore, BAY-091 and BAY-297 serve as valuable chemical probes to study PIP4K2A signaling and its involvement in pathophysiological conditions such as Cancer.

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