p300 catalytic inhibition selectively targets IRF4 oncogenic activity in multiple myeloma (RPMI8226_KB528_timeseries)

The oncogenic transcription factor (TF) IRF4 is a universal multiple myeloma (MM) dependency that remains undrugged owing to its disordered structure. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic approach to nominate druggable TF cofactors, we identified the chromatin coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. We developed KB528, a highly selective p300 KAT inhibitor to explore the regulatory relationship between IRF4 and p300. Instead of broadly inhibiting transcription, partial p300 KAT inhibition selectively downregulates IRF4 and its downstream gene expression program leading to apoptosis selectively in MM cells. IRF4 dependency is a hallmark of MM that exists downstream of existing MM therapies. Consequently, p300 KAT inhibition exhibits strong antiproliferative activity ex vivo and in vivo as a single agent as well as in combination regimens in treatment refractory models. p300 KAT inhibition is well-tolerated in vivo motivating further clinical development in MM. Overall design: RPMI-8226 cells at 0 (DMSO), 1, 3, 6, and 24 hour treated with 100 nM KB528 (p300 KAT inhibitor).

致癌转录因子（Transcription Factor, TF）IRF4是多发性骨髓瘤（Multiple Myeloma, MM）的广谱依赖型靶点，因其结构无序性至今尚未实现药物靶向干预。本研究采用转录调控网络（Transcriptional Regulatory Network, TRN）图谱分析技术——一种可无偏筛选可靶向转录因子辅因子的多组学方法，鉴定出染色质共激活因子赖氨酸乙酰转移酶（Lysine Acetyltransferase, KAT）p300为IRF4的关键互作伴侣蛋白。我们开发了高选择性p300 KAT抑制剂KB528，用以探究IRF4与p300之间的调控关联。研究发现，与广谱抑制转录不同，部分抑制p300 KAT活性可选择性下调IRF4及其下游基因表达程序，进而仅在MM细胞中诱导细胞凋亡。IRF4依赖是MM的标志性特征，且该特征存在于现有MM治疗方案的下游通路中。因此，p300 KAT抑制剂无论是作为单药还是联合治疗方案，在治疗耐药模型中均展现出显著的体内外抗增殖活性。此外，p300 KAT抑制剂在体内具有良好的耐受性，为其在MM中的进一步临床开发提供了坚实依据。实验整体设计：使用100 nM KB528（p300 KAT抑制剂）处理RPMI-8226细胞，分别在0小时（二甲基亚砜DMSO对照组）、1小时、3小时、6小时及24小时收集样本。