Fairhurst, Robin, Caravatti, Giorgio, Furet, Pascal, Imbach-Weese, Patricia, Stauffer, Frederic, Rueeger, Heinrich, Mccarthy, Clive, Ripoche, Sebastien, Oswald, Susanne, Arnaud, Bertrand, Jary, Aline, Maira, Michel, Schnell, Christian, Guthy, Daniel Alexander, Wartmann, Markus, Kiffe, Michael, Desrayaud, Sandrine, Blasco, Francesca, Widmer, Toni, Seiler, Frank Hans, Gutmann, Sascha and Knapp, Mark (2022) Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor. Journal of medicinal chemistry, 65 (12). pp. 8345-8379. ISSN 1520-4804

Abstract

Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.

Item Type:	Article
Keywords:	Aminopyridines Antineoplastic Agents Cell Line, Tumor Organic Chemicals Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors
Date Deposited:	18 Oct 2022 00:45
Last Modified:	18 Oct 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46613