Gardberg Anna S, Huhn Annissa J, Cummings Richard, Bommi-Reddy Archana, Poy Florence, Setser Jeremy, Vivat Valerie, Brucelle Francois, Wilson Jonathan
Drug Discovery, Constellation Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
Foghorn Therapeutics, Cambridge, Massachusetts 02142, USA.
Struct Dyn. 2019 Oct 11;6(5):054702. doi: 10.1063/1.5119336. eCollection 2019 Sep.
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme.
组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）催化蛋白质的动态可逆乙酰化，这是一种与多种癌症相关的表观遗传调控机制。事实上，HDAC抑制剂已在临床上获得批准。HAT旁系同源物p300和CREB结合蛋白（CBP）已被证明与包括几种血液系统恶性肿瘤和雄激素受体阳性前列腺癌在内的人类病理状况有关。其他人报道了具有细胞活性的p300和CBP的辅酶A竞争性抑制剂。在此，我们描述了通过p300-HAT高通量筛选发现的2种化合物CPI-076和CPI-090，它们通过结合变构位点抑制p300-HAT。我们展示了这些分子与p300-HAT一个先前未描述的变构位点结合的高分辨率（1.7和2.3 Å）共晶体结构。衍生化产生了可操作的构效关系，但全长酶活性测定表明，这个变构HAT抑制剂系列是人为的，仅抑制p300的HAT结构域，对全长酶没有影响。
