1区 · 医学
Article
作者: Knapp, Mark ; Jary, Aline ; Rueeger, Heinrich ; Wartmann, Markus ; Caravatti, Giorgio ; Furet, Pascal ; Kiffe, Michael ; Imbach-Weese, Patricia ; Schnell, Christian ; Desrayaud, Sandrine ; McCarthy, Clive ; Blasco, Francesca ; Gutmann, Sascha ; Widmer, Toni ; Fairhurst, Robin A. ; Oswald, Susanne ; Seiler, Frank ; Maira, Michel ; Arnaud, Bertrand ; Ripoche, Sebastien ; Stauffer, Frédéric ; Guthy, Daniel A.
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.