Abstract 4492: A novel and potent FLT3 and IRAK4 dual inhibitor for the treatment of acute myeloid leukemia

Abstract

Abstract Several potent FMS-like tyrosine kinase 3 (FLT3) inhibitors have been developed and approved for the treatment of FLT3-mutant acute myeloid leukemia (AML) recently. These inhibitors block the signaling pathways involved in proliferation of leukemic cells, and have shown favorable initial results in early-stage AML patients. However, a significant percentage of patients relapsed with poor prognoses. The relapse is generally caused by a compensatory innate immune stress response, such as Toll-like receptor activation, which induces adaptive resistance to the FLT3 inhibition. Interleukin-1 receptor associated kinase 4 (IRAK4) functions as a mediator of Toll-like receptor and interleukin-1 receptor signaling pathways. Patients harboring a U2AF1 or SF3B1 spliceosome mutation were found to express a longer and more active isoform of IRAK4 kinase, which could result in lasting activation of NF-κB and MAPK in oncogenic and innate immune signaling. Emavusertib (CA-4948), an IRAK4/FLT3 inhibitor, is currently in phase I clinical trials. To address the critically unmet medical needs of myeloid leukemia patients, we have developed a novel and potent FLT3 and IRAK4 dual inhibitor HPB-092 with excellent selectivity to provide durable efficacy in myeloid malignancies by eliminating adaptive resistance. HPB-092 significantly inhibited MV4-11 tumor cell proliferation at low nanomole concentration. HPB-092 demonstrated good oral bioavailability in several animal species. In a disseminated MV4-11 xenograft mouse model, HPB-092 displayed strong anti-tumor activity at 5mg/kg. HPB-092 was well-tolerated with no obvious adverse events at a dose of 40 mg/kg in two-weeks safety study in SD rats. In addition, no rhabdomyolysis side-effect was observed upon histological analysis. These results underscore the potential therapeutic benefit and safety profile of HPB-092 for the treatment of AML, especially in patients with mutations in U2AF1 or SFF3B1 spliceosome. Citation Format: Rui Yang, Lei Wu, Bing Zhang, Michael Xiang, Suyue Wang, Camille Xiang, Zhijian Lu, Jason Xiang. A novel and potent FLT3 and IRAK4 dual inhibitor for the treatment of acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4492.