Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands

Abstract

The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10 to 100 fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound 6 (dBRD9) as a tool for the study of BRD9.

Plasticity in binding confers selectivity in ligand-induced protein degradation

“…Recruitment of this target protein to the E3 ubiquitin ligase facilitates ubiquitination and subsequent degradation of the target protein 22 . This principle has been successfully applied to several targets including the Bromodomain and Extra Terminal (BET) family (BRD2, BRD3, BRD4), RIPK2, BCR-ABL, FKBP12, BRD9, and ERRα 2,4,6,23–26 and represents a promising new pharmacologic modality now widely explored in chemical biology and drug discovery.…”

A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader

“…To date, VHL- and CRBN-mediated protein degraders have been developed for several targets, including: BRD4 (Lu et al, 2015; Winter et al, 2015; Zengerle et al, 2015), FKBP12 (Winter et al, 2015), BRD9 (Remillard et al, 2017) and for the kinases BCR-ABL (Lai et al, 2016), RIPK2 (Bondeson et al, 2015) and CDK9 (Olson et al, in press). Several reports described the importance of varying all three components of degrader molecules, namely the warhead, the linker and the E3 ligase ligand, to optimize degradation efficiency (Bondeson et al, 2015; Lai et al, 2016; Zengerle et al, 2015).…”

Advancements in the Development of non‐BET Bromodomain Chemical Probes

“…[91] Bradner and co-workersh ave disclosed dBRD9 (73)t he first BRD9 PROTAC (Figure 11 c). [92] As election of BRD9 PROTACs were synthesized based around three different BRD9c hemical probes, LP99, I-BRD9, both of which were reviewed previously, [13] and 58 discussed above.C ompound 58 was eventually chosen to functiona st he selective BRD9 inhibitor part of the PROTAC, due to improved BRD9 selectivity (in particular,o ver the BET subfamily) when compared with LP99 and I-BRD9 PROTAC derivatives, highlighting the advances that have been made in BRD9 chemical probe development since our last review.T oc omplete the bifunctionalP ROTAC, an E3 ligase recruiter (a pomalidomidec onjugate) was appended via ap olyethylene glycol (PEG) chain to produce 73.C ompound 73 maintained potencyf or BRD9 (pIC 50 = 7.0) and selectivity over the BET subfamily (BRD4(1)p IC 50 < 4.3). BRD9 was selectively degraded over ar ange of potencies using 73 (BRD9 pDC 50 = 7.0).…”

“…As discussed previously,G enentech and Constellation Pharmaceuticals have reported selective bromodomain inhibitors where selectivity can be attributed to bromodomain specific interactions with the conserved water network found within the bromodomain binding pocket. [86] Substitution of the Nmethyl group of hit molecule 62 for a1 -butene group (92) dramatically reduced the potencyf or BRD4, BRD9, BRPF1, CREBBP and CECR2,w hilst maintaining sub-micromolar potency for TAF1(2)( pIC 50 = 7.3) (Figure 15 c). Compound 92 was subjected to iterative structure-based design leading to TAF1(2)/TAF1L(2) chemical probe GNE-371 (93).…”