CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

CCS1477 (inobrodib) 是一种有效的选择性 EP300/CBP bromodomain 抑制剂，可在血液恶性肿瘤模型系统中诱导细胞周期停滞和分化。在骨髓性白血病细胞中，它促进 EP300/CBP 从以强 MYB 占据和高 H3K27 乙酰化为标志的增强子亚群中快速驱逐，同时下调从属致癌网络并重新分布到靠近分化基因的位点。在骨髓瘤细胞中，CCS1477 诱导 EP300/CBP 从常见 (4; 14) 易位的靶标FGFR3中驱逐，并从 IRF4 占据的位点重新分布到 TCF3/E2A 占据的位点。在一部分患有复发或难治性疾病的患者中，CCS1477单一疗法可诱导 AML 的分化反应和经过大量预处理的多发性骨髓瘤的客观反应。体内临床前联合研究揭示了对标准护理药物治疗的协同反应。因此，CCS1477 通过破坏 EP300/CBP 向关键转录因子占据的增强子网络的募集而表现出令人鼓舞的临床前和早期临床活性。