China
Africa
Explore chapters and articles related to this topic
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
In addition to a VHL ligand, the PROTAC platform uses thalidomides to recruit Cereblon (CRBN) that is part of the cullin 4 (CUL4) containing E3 ubiquitin ligase complex CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN). Thalidomide-based drugs were developed initially as a sedative, but were withdrawn owing to teratogenicity (Bartlett et al., 2004). Nevertheless, thalidomides have been repurposed for the treatment of leprosum, multiple myeloma, and 5-q-deletion-associated dysplasia. By ligand-affinity chromatography, CRBN was identified as the target of thalidomides (Ito et al., 2010). Moreover, several groups, including Dr. Bradner’s group, have reported that thalidomides modulate the activity of E3 ubiquitin ligase in CRL4CRBN and promote ubiquitylation of IKAROS family transcription factors (IKZF1 and IKZF3) (Fischer et al., 2014; Kronke et al., 2014; Lu et al., 2014), casein kinase 1a (Kronke et al., 2015; Petzold et al., 2016), translation termination factor GSPT1 (Matyskiela et al., 2016), and zinc finger protein ZFP91 (An et al., 2017). Subsequently, Dr. Bradner’s group hypothesized that a rational design of bifunctional thalidomides-conjugated ligands could induce CRBN-dependent degradation of target proteins. To test the hypothesis, they developed a hybrid molecule named dBET consisting of a thalidomide derivative and JQ1, a ligand of bromodomain and extra-terminal (BET) proteins (Winter et al., 2015; Winter et al., 2017). dBET shows potent and CRBN-dependent degradation activity of BET protein in vitro at 100 nM. In addition, dBET induces BET protein degradation and delays leukemia progression in a tumor xenograft model. Dr. Crews’ group also developed a similar hybrid molecule named ARV-825 that shows potent activity to degrade BRD4 protein (Lu et al., 2015). After this achievement, many groups have developed CRBN-recruiting PROTACs against various oncogenic proteins such as BCR-ABL (Lai et al., 2016), BRD9 (Remillard et al., 2017), EML4-ALK (Powell et al., 2018; Zhang et al., 2018), fms related tyrosine kinase 3 (FLT3) (Huang et al., 2018), Bruton’s tyrosine kinase (BTK) (Buhimschi et al., 2018), and CDK9 (Olson et al., 2018).
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
Also published from the Dana-Farber Cancer Institute in 2017 was a filing that exemplified PROTACs capable of degrading BRD9 [144]. This target is part of the SWI/SNF nucleosome remodeling complex [145], and has been identified as a potential anti-cancer drug target. Exemplified compounds employed both cereblon and VHL E3 ligase binders, and incorporated target binding ligands that have been reported to be selective for BRD9 inhibition over other bromodomain-containing proteins [146,147]. In particular, although no discrete DC50 or Dmax values were reported in this filing, 1 h treatment with 100 nM of compound 63Figure 16 was described as causing near complete BRD9 loss in MOLM-13 cells with off-target loss of BRD4 and BRD7 only occurring at concentrations >500 nM. Furthermore, compound 64Figure 16 was reported as having high degradation selectivity for BRD9 over BRD4 and BRD7 even at concentrations up to 5 µM. This filing was followed several years later by a BRD9 PROTAC filing from C4 Therapeutics [148]. This filing exemplified a small number of cereblon-based compounds, of which selected examples (e.g. compound 65, Figure 16) were claimed to degrade BRD9 with DC50 potency <100 nM in Jurkat cells.
Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities
Published in Expert Review of Anticancer Therapy, 2019
Krystal A Orlando, Vinh Nguyen, Jesse R Raab, Tara Walhart, Bernard E Weissman
Recent studies have suggested that inactivation or loss of one subunit of the SWI/SNF complex may impact its composition, resulting in significant functional changes [150,151,162,163]. Co-inactivation of SMARCB1 and SMARCA2 expression occurs in cell lines and primary tumors, including RTs [89,164,165]. The concomitant loss of SMARCB1, SMARCA2, and PBRM1 expression was detected in two epithelioid sarcomas with pure rhabdoid features [164,166]. These results suggest that the loss of SMARCB1 works in tandem with other SWI/SNF core subunits to drive tumorigenesis. Several recent reports underscore the impact of changes in the subunit composition of the SWI/SNF complex upon its normal activities. Mashtalir et al. have described the assembly of subcomplexes that ultimately unite to form the full SWI/SNF complex [167]. Importantly, they also show that many of the subunit mutations found in human cancers alter the normal assembly of SWI/SNF complexes resulting in aberrant forms [167]. Another recent report demonstrated that inhibition of BRD9, an SWI/SNF subunit that can appear in abnormal complexes induced by mutations in other subunits, can reactive epigenetically silenced genes in tumors [168]. They also demonstrated that BRD9 could regulate the activity of SWI/SNF through phosphorylation of the SMARCA4 ATPase subunit [168]. Overall, these findings emphasize the critical need for further studies on the composition and activities of the SWI/SNF complex in cancers drive by mutations in different subunits, especially for identifying novel avenues for therapeutic interventions.
PROTACs for BRDs proteins in cancer therapy: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chao Wang, Yujing Zhang, Shanbo Yang, Wujun Chen, Dongming Xing
BRD9 is a BRD-containing subunit of BAF (BRG-/BRMassociated factor). BAF is a variant of the SWI/SNF complex that regulates gene expression, DNA replication, and DNA repair. Overexpression of BRD9 can lead to cancer development. In 2017, Remillard et al. first developed BRD9 PROTACs by linking BRD9 inhibitor BI-7273 and CRBN ligand pomalidomide47. PROTAC 11 (Figure 6) was found to induce degradation of BRD9. It has a significant selectivity for BRD9 over BRD4 and BRD7. Compared to its parental inhibitor BI-7273, PROTAC 11 exhibited 10–100-fold potency in degrading BRD9 with DC50 and IC50 values of 50 and 104 nM, respectively. The CRBN-based PROTAC targeting BRD9 seems to be a potential strategy for human acute leukaemia treatment.