Identification of 3,5-Dimethylisoxazole Derivatives as BRD4 Inhibitors for the Treatment of Colorectal Cancer

Yifei Yang; Lincheng Fang; Pan Chen; Huibin Zhang; Jinpei Zhou

doi:10.1021/acsmedchemlett.0c00294

Identification of 3,5-Dimethylisoxazole Derivatives as BRD4 Inhibitors for the Treatment of Colorectal Cancer

ACS Med Chem Lett. 2020 Aug 31;11(11):2174-2181. doi: 10.1021/acsmedchemlett.0c00294. eCollection 2020 Nov 12.

Authors

Yifei Yang^{1

2}, Lincheng Fang³, Pan Chen¹, Huibin Zhang³, Jinpei Zhou¹

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
³ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.

Abstract

Bromodomain-containing protein 4 (Brd4) plays a critical regulatory role in gene transcription that has been recently recognized as a promising strategy for cancer therapy. Based on the BRD4 protein containing two tandem bromodomain structures, BD1 and BD2, we designed and synthesized a series of 3,5-dimethylisoxazole derivative dimers targeting both bromodomains simultaneously to enhance protein binding potency. Among them, compound 22 significantly inhibited the proliferation of colorectal cancer cells HCT116 (IC₅₀ = 162 nM), with a 20-fold increase in antiproliferative activity compared to inhibitor 14. The results of WesternBlot showed that compound 22 could down-regulate c-MYC protein levels and up-regulate HEXIM1 expression and modulate apoptosis through intrinsic pathways. In addition, compound 22 exhibited outstanding antitumor efficacy in the CT-26 tumor mouse model with a tumor suppression rate of 56.1%. Taken together, 3,5-dimethylisoxazole derivative dimer 22 has remarkable protein inhibitory effect and antitumor activity in vitro and in vivo. A protein binding model of compound 22 is being further analyzed, which will facilitate the development of bivalent BRD4 inhibitors and probe the biological function of BRD4.