Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor.

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.

• Authors: Robin A Fairhurst, Pascal Furet, Patricia Imbach-Weese, Frédéric Stauffer, Heinrich Rueeger, Clive McCarthy, Sebastien Ripoche, Susanne Oswald, Bertrand Arnaud, Aline Jary, Michel Maira, Christian Schnell, Daniel A Guthy, Markus Wartmann, Michael Kiffe, Sandrine Desrayaud, Francesca Blasco, Toni Widmer, Frank Seiler, Sascha Gutmann, Mark Knapp, Giorgio Caravatti
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 12 Pg. 8345-8379 (06 23 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35500094 (Publication Type: Journal Article)

Chemical References

• Aminopyridines
• Antineoplastic Agents
• CLR457
• Organic Chemicals
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors

Topics

• Aminopyridines (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Organic Chemicals
• Phosphatidylinositol 3-Kinases
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)