Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP

Abstract

p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain which is inhibited by the small molecule A-485 and an acetyl-lysine binding bromodomain which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 chromatin binding directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.

Combined Targeting of the BRD4–NUT–p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734

“…18). The p300 bromodomain has been described as important for its chromatin occupancy (19), protein-protein interactions (20), and even HAT activity (21). We found that GNE-781 treatment exhibited selective growth inhibition of BRD4-NUTþ NMC cell lines, TC-797 ( 22), 10-15 (9), and PER-403 ( 23) with low nanomolar potency, although limited efficacy, compared with non-NMC cell lines, COS7, U2OS, and 293T (Fig.…”

Nrf2–ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms

“…Additionally, CBP also acts as a scaffold to stabilize other components of the general transcriptional machinery. p300/CBP also acetylate histones that render decondensation of chromatin and subsequent recruitment of the transcriptional machinery (Tonelli et al, ; Zucconi et al, ). Apart from this role, both CBP and p300 are reported to acetylate Lys438, Lys 443, Lys 445, Lys 533, Lys536, Lys538, Lys588, and Lys591 of NEH1 domain of Nrf2 and thus adds to its DNA binding ability.…”

Using Chemical Epigenetics to Target Cancer

“…This strategy disrupts enhancer RNA production, which is known to suppress EP300/CBP activity (Bose et al, 2017), and, as a result, suppresses the transcription of enhancer regulated genes (Raisner et al, 2018). Intriguingly, targeting both domains simultaneously dramatically delocalizes EP300/CBP from chromatin at promoters to synergistically inhibit prostate cancer cell proliferation (Zucconi et al, 2019). These intriguing studies highlight the distinct functional roles of each domain within EP300 and CBP and the utility of targeting multidomain proteins using distinct inhibitors targeted against individual domains.…”