molecules of the month

Context. NVP-CLR457 (Novartis Institutes for BioMedical Research) is an oral, non-CNS-penetrating pan-class IA phosphoinositide 3-kinase (PI3K) inhibitor. Due to the key involvement of PI3K in the famed PI3K-Akt−mTOR pathway, whose deregulation has been observed in several cancers, it is no surprise that the last decade has seen over 600 medicinal chemistry-based publications and patents focusing on inhibitors targeting at least one of the 4 class I PI3K isoforms (α, β, δ, and γ). Consequently, over 30 anti-PI3K clinical candidates have been developed during this time, culminating in the approval of 5 isoform-selective agents: idelalisib (PI3Kδ), copanlisib (PI3Kα/δ), duvelisib (PI3Kδ/γ), alpelisib (PI3Kα), and the recently withdrawn umbralisib (PI3Kδ, CK1ε). This is a great teaching example for medicinal chemistry as the authors…