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
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...
May 2, 2022: Journal of Medicinal Chemistry