Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold

Abstract

Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.

Dual‐target inhibitors of bromodomain and extra‐terminal proteins in cancer: A review from medicinal chemistry perspectives

“…Through epigenetic compound library screening performed in a human haploid reporter cell line, a small compound inhibitor with high affinity to the second BRD of TAF1 showed a comparable relief of heterochromatin silencing and MYC transcription inhibition as seen with JQ1 treatment or knockdown of BRD4 but not other BET proteins,159 indicating a functional association between TAF1 F I G U R E 15 Dual-target inhibitors of BET bromodomains and other non-kinases and dual PROTAC of BET and PLK1and BRD4 in transcriptional regulation159 and providing a proof-of-concept for developing dual-target inhibitors against TAF1 and BRD4. With the BI-2536 chemical scaffold, Remillard et al160 used a structure-guided design and identified compound 64 as a highly effective dual inhibitor of TAF1(2) and BRD4(1), with IC 50 values of 16 and 37 nM for TAF1(2) and BRD4(1), respectively (Figure15).…”

Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors

“…CeMMEC13 ( 2 ) was disclosed by Sdelci and co-workers as a TAF1 inhibitor, and researchers from Bayer developed BAY-299 ( 3 ), a potent inhibitor of both TAF1(2)/TAF1L(2) and BRPF2 . Compound 4 was developed from polo-like kinase 1 inhibitor BI-2536 and demonstrates >120-fold selectivity for TAF1(2) over BRD4(1) . Bifunctional molecule 5 was designed to bind to both bromodomains of TAF1 bivalently and demonstrated significant affinity gain over monovalent ligand binding .…”

“…It has been previously demonstrated that TAF1(2) is able to recognize not just methyl acetyl lysine, but also atypical crotonyl and butyryl substituted acetyl lysines . Genentech and Constellation Pharmaceuticals have elegantly utilized this facet of the TAF1(2) bromodomain with the 1-butenyl group as an atypical acetyl lysine methyl mimetic on a pyrrolopyridinone scaffold to induce TAF1(2) selectivity through the rearrangement and stabilization of the KAc binding site water molecules. , This approach was also successfully applied to a dihydropyridopyrazine scaffold in the development of a dual BET, TAF1(2) inhibitor 4 . Overlaying the published structure of GNE-371 bound to TAF1(2) with 18 bound to TAF1(2) indicated that the methyl groups occupied approximately the same space, even if the angle of the C–C bond was slightly different (Supporting Information Figure S1).…”

“…18 Compound 4 was developed from polo-like kinase 1 inhibitor BI-2536 and demonstrates >120-fold selectivity for TAF1(2) over BRD4(1). 19 Bifunctional molecule 5 was designed to bind to both bromodomains of TAF1 bivalently and demonstrated significant affinity gain over monovalent ligand binding. 20 Additionally, a bivalent molecule designed to inhibit the BET bromodomains was also reported to inhibit TAF1(2), although it is unclear whether the TAF1 inhibition is bivalent.…”

“…22,23 This approach was also successfully applied to a dihydropyridopyr- azine scaffold in the development of a dual BET, TAF1(2) inhibitor 4. 19 Overlaying the published structure of GNE-371 bound to TAF1(2) with 18 bound to TAF1(2) indicated that the methyl groups occupied approximately the same space, even if the angle of the C−C bond was slightly different (Supporting Information Figure S1). Accordingly, compound 24 bearing a 1butenyl acetyl lysine methyl mimetic was accessed.…”