Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

Abstract

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.

Keywords: ELT; Encoded Library technology; PI3K p110α (H1047R); PI3Kα; p110α.

Figure 1

Design of DEL-A: “null” indicates that the reaction was carried out without addition of the desired BB amino acid (R¹) or boronate (R²).

Figure 2

PI3Kα wild type selection (left), mutant (H1047R) selection (middle), and mutant selection with ZSTK474competitor (right). Library members with a single copy were removed to simplify visualization.

Scheme 1. Selected Building Blocks at Cycle 3 (1) and Cycle 2 (2, 3, and 4)

Scheme 2. Inhibitor Pharmacophore Defined by Selection Analysis

Scheme 3. Synthesis of the Target Off-DNA Compounds

Figure 3

X-ray structure of 5e bound to PI3Kα: (a) key interactions of the inhibitor in the active site depicted; (b) surface representation of the active site with the bound inhibitor demonstrates steric packing and interactions with the residues of the P-loop.