Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chemistry with over 600 medicinal chemistry-based publications and patents appearing to date, leading to 38 clinical candidates and the launch of 2 drugs, idelalisib in 2014 and copanlisib in 2017. This perspective will discuss medicinal chemistry design approaches to novel isoformselective inhibitors through considering brief case histories of compounds that have progressed 2 either into clinical development or that have revealed new structural motifs in this highly competitive area of research.

PI3K inhibitors: review and new strategies

“…Recent reviews provide a comprehensive coverage of pan-PI3K inhibitors, PI3Ka specic inhibitors and PI3K/mTOR inhibitors, their status and the specic cancers that they target. [35][36][37][38] We thus refer the readers to these. Here we provide a mere brief overview (Fig.…”

“…The chemical and conformational differences of these regions among the isoforms define their distinct interactions and have been meticulously probed with the hope that such analyses would help in improving inhibitor specificity. 35 The ATP binding site in PI3K isoforms is between the two lobes of the kinase domain, which are separated by a hinge. This is where the adenine ring of ATP and the inhibitors' rings anchor.…”

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

“…We will first present a road-map of the various regions of the ATP-binding site, and then discuss the influence of these regions on the selectivity of various isoform selective inhibitors. The extensive literature on PI3K inhibitors, which has been the subject of a recent review (418 patents and 192 medicinal chemistry publications since 2012 [64]), precludes a detailed analysis of every inhibitor. In this review, we have chosen to concentrate on inhibitors with published data on isoform selectivity as well as structural information on binding mode, and particularly those inhibitors that yield insight into general principles of the structural determinants of isoform selectivity.…”

“…In this review, we will first focus on the available structural information for each of the isoforms, and then how this informs isoform selective inhibitor design and development. Pan PI3K inhibitors have been reviewed in detail elsewhere and will not be addressed in this review [64].…”

Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation

“…2,3 The medicinal potential of PI3Ks as therapeutic targets for human malignancies has been validated by an increasing amount of research, as well as the clinical development of numerous inhibitors that ablate aberrant PI3K signaling. [4][5][6] According to their kinase specificity, they are divided into three classes, including pan-class I PI3K inhibitors, PI3K/mTOR dual inhibitors, and subtype-selective PI3K modulators.…”