Discovery and optimization of 1-(1 H -indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer

Xiang, Qiuping; Wang, Chao; Zhang, Yan; Xue, Xiaochang; Song, Ming; Zhang, Cheng; Li, Chenchang; Wu, Chen; Li, Kuai; Hui, Xiaoyan; Zhou, Yulai; Smaill, Jeff B.; Patterson, Adam V.; Wu, Donghai; Ding, Ke; Xu, Yong

doi:10.1016/j.ejmech.2018.01.087

Cited by 51 publications

(41 citation statements)

References 45 publications

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“…TwoC REBBP/EP300 inhibitors have been developed by Xiang and co-workers,b ased arounda1-(1H-indol-1-yl)ethanone chemotype (Figure 7a). [54] Commencing with af ragment based virtuals creen, fragment 26 was subsequently optimized to deliver inhibitor 27 using X-ray crystallography driven SAR. The carboxylic acid was shown to form aw ater-mediated hydrogen bond to Arg1173 and provedv ital to CREBBPp otency.…”

Section: Crebbp/ep300mentioning

confidence: 99%

“…Initial hit compound 52 was selected as ap romising start point for the development of BRPF1/2/3i nhibitors due to possessing micromolar potency for BRPF1 (pIC 50 = 5.3) and excellent ligand efficiency (LE = 0.62) ( Figure 9d). Optimization of the scaffold, in particular the introductiono fa na-methyl group andg rowth towardt he WPF shelf, led to NI-42 (53)a nd NI-57 (54) ( Figure 9h). [75] Compound 53 demonstrated potency for BRPF1/2/3 (pIC 50 = 8.1/7.3/6.6) and selectivity over the BET bromodomains ( 600).…”

Section: Brpf1/2/3mentioning

confidence: 99%

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Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets.

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Section: Crebbp/ep300mentioning

confidence: 99%

Section: Brpf1/2/3mentioning

confidence: 99%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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“…More importantly, CBP/p300‐modified nonhistone substrates also play critical roles in cancer progression . SGC‐CBP30, a compound that exhibits high selectivity for CBP/P300, markedly inhibits cell growth in several prostate cancer cell lines . Curcumin, a natural product extracted from Curcuma longa , has been recognized as a p300/CBP inhibitor of histone acetyltransferase activity.…”

Section: Targeting Novel Dynamic Ptms In Cancer Therapymentioning

confidence: 99%

Advances of Proteomics in Novel PTM Discovery: Applications in Cancer Therapy

Wang

Zhang

et al. 2019

Small Methods

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Protein posttranslational modification (PTM) is a critical mechanism to enhance the diversity of protein species and functions in organisms. Currently, many different PTMs are discovered and found to be involved in a wide range of cellular processes. The aberrant regulation of PTM dynamics is reported to contribute to cancer development. Phosphorylation and acetylation are the best studied PTMs, and the application of high‐resolution mass spectrometry‐based proteomics and specific antibody‐based enrichment technologies significantly promotes novel PTM discovery. This review discusses methods for global PTM identification, including antibody‐based enrichment and chemical probe‐based identification. Several acylations, such as propionylation, butyrylation, succinylation, malonylation, and crotonylation, are recently found to influence both histone and nonhistone proteins and to be intimately linked with the progression of cancer. It is proposed that targeting novel PTM dynamics by pharmacological inhibitors has great potential for cancer therapy.

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“…CBP/p300 proteins have an oncogenic role in PCa in a cellular context‐dependent manner (Ding et al , ; Zhong et al , ), consistent with the finding that p300 is often deregulated in PCa patient samples (Debes et al , ). Tool compound small molecule CBP/p300 bromodomain inhibitors have demonstrated an important role for this domain in the coactivator functions of CBP/p300 and significant dose‐dependent inhibition of AR signaling and PCa proliferation in vitro and in vivo (Comuzzi et al , ; Heemers et al , ; Lasko et al , ; Xiang et al , ).…”

Section: Introductionmentioning

confidence: 99%

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

Yan

Wang

et al. 2019

EMBO Mol Med

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CULLIN3‐based E3 ubiquitin ligase substrate‐binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient‐derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non‐hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti‐cancer efficacy of NEO2734 in SPOP‐mutated PCa patients.

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Discovery and optimization of 1-(1 H -indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer

Cited by 51 publications

References 45 publications

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Advances of Proteomics in Novel PTM Discovery: Applications in Cancer Therapy

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

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