Characteristics of anticancer activity of CBP/p300 inhibitors – Features of their classes, intracellular targets and future perspectives of their application in cancer treatment

IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacology & Therapeutics Pub Date : 2024-03-22 DOI:10.1016/j.pharmthera.2024.108636
Magdalena Strachowska , Agnieszka Robaszkiewicz
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引用次数: 0

Abstract

Due to the contribution of highly homologous acetyltransferases CBP and p300 to transcription elevation of oncogenes and other cancer promoting factors, these enzymes emerge as possible epigenetic targets of anticancer therapy. Extensive efforts in search for small molecule inhibitors led to development of compounds targeting histone acetyltransferase catalytic domain or chromatin-interacting bromodomain of CBP/p300, as well as dual BET and CBP/p300 inhibitors. The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity.

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CBP/p300 抑制剂的抗癌活性特征--其类别特征、细胞内靶点及其在癌症治疗中的应用前景。
由于高度同源的乙酰转移酶 CBP 和 p300 对癌基因和其他促癌因子的转录升高有促进作用,因此这些酶可能成为抗癌治疗的表观遗传学靶标。在寻找小分子抑制剂的广泛努力下,开发出了以组蛋白乙酰转移酶催化结构域或 CBP/p300 的染色质相互作用溴结构域为靶点的化合物,以及 BET 和 CBP/p300 双重抑制剂。CCS1477 和 NEO2734 在体外和小鼠模型中具有良好的抗癌效果,因此已进入临床试验阶段。然而,由于 CBP/p300 与其他酶的关键功能域具有相似性,而这些酶与癌症进展密切相关,且其拮抗剂在癌症治疗中表现出显著的临床疗效,因此所描述的抑制剂中没有一种对 CBP/p300 具有完全特异性。因此,我们对 CBP/p300 抑制剂可能存在的与临床相关的非靶点进行了修订,这些非靶点可与 CBP/p300 同时阻断,从而提高 CBP/p300 抑制剂的抗癌潜力以及药代动力学预测数据,如吸收、分布、代谢、排泄(ADME)和毒性。
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来源期刊
CiteScore
23.00
自引率
0.70%
发文量
222
审稿时长
90 days
期刊介绍: Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.
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