We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.

我们基于支架跳跃策略并使用基于合理结构的设计开发了一系列口服有效的IRAK4抑制剂。在我们先前报道的吡咯并嘧啶系列（Scott等人，2017）中，为解决低渗透性和高流出问题所做的努力导致了对吡咯并三嗪的鉴定，该吡咯并三嗪含有较少的形式氢键供体，本质上具有更高的亲脂性。进一步优化该吡咯并三嗪核心上的取代基，最终发现了30个有前途的体内探针，用于评估IRAK4抑制与BTK抑制剂联合治疗MyD88突变DLBCL的潜力。在具有双重MyD88 / CD79突变（OCI-LY10）的ABC-DLBCL模型中进行测试时，30 与依鲁替尼联用证明肿瘤消退。