From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

Abstract

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

Keywords: Amides; BET inhibitors; JQ1.

Figure 1.

Selected BET inhibitors reported in the literature

Figure 2.

JQ1 derived PROTAC compounds

Figure 3.

Comparison of ligand binding modes of BET family members. Crystal structure of BRD2/BD2 in complex with (A) 7 (magenta, PDB: 6WWB) and (B) JQ1, 1a, (yellow, PDB: 3ONI). (C) Crystal structure of birabresib, 1c, bound to BRD4/BD1 (purple, PDB: 5WMD). Hydrogen bonds are shown as dotted lines.

Figure 4.

High-resolution structures of JQ1 derivatives bound to BRD4(BD1). (A) 1k interacts with Asn140, Asp144, and Leu92 (PDB: 7RN2). (B) 1q interacts with Asn140 and Tyr139 (PDB: 7RMD). (C) JQ1 1a (PDB: 3MXF) interacts with Asn140 and Asp144. (D) birabresib 1c (PDB: 5WMD) interacts with Asn140, Asp144, and Leu92. Dotted lines represent hydrogen bonds and red spheres represent ordered water molecules. Ligand electron densities are shown in SI Fig S2.

Scheme 1.

Synthesis of amide derivatives