Abstract 547: HPB-092: A novel FLT3 and IRAK4 dual inhibitor for the treatments of AML and MDS

Activating mutations in the Tyrosine kinase FLT3 occur in about 25% of acute myeloid leukemias (AML)1 and selective FLT3 inhibitors are clinically effective and have been recently approved by FDA for patients with relapsed/refractory AML with FLT3 mutations. While effective, a significant challenge with current FLT3 inhibitors is the rapid development of resistance through mechanisms including additional FLT3 mutations, CYP3A4 upregulation, or adaptive resistance through activation of parallel signaling pathways. It has been recently shown that an important mechanism of adaptive resistance to FLT3 inhibitors involves activation via Interleukin-1 receptor-associated kinase 4 (IRAK4) pathway2. Concomitant inhibition of FLT3 and IRAK4 could, therefore, enhance efficacy and durability in FLT3 mutant AML. We have developed HPB-092, a highly selective, novel FLT3/IRAK4 dual inhibitor. In biochemical assays, HPB-092 demonstrated potent inhibitory activity against FLT3-ITD (IC50 = 0.24 nM), FLT3-D835Y (IC50 = 0.18 nM), and IRAK4 (IC50 = 3.1 nM). HPB-092 effectively inhibited the proliferation of MV4-11, a FLT3-ITD mutant cell line at IC50 = 6.5 nM, and displayed excellent kinase selectivity in the Eurofins ScanEDGE assay at 1 uM. HPB-092 did not inhibit CYP3A4 up to 50 uM or hERG at concentrations up to 10 uM. In mouse tumor xenograft models of FLT3 mutant leukemias (MV4-11 and MOLM-13 cells), HPB-092 exhibited dose dependent efficacy and regression of established tumors. A 28-day GLP-compliant toxicity study showed HPB-092 was well tolerated in rats (NOAEL: 75 mg/kg/day) and dogs (NOAEL: 24 mg/kg/day), with no test article-related genotoxicity or safety pharmacology findings. Compared to the approved FLT3 inhibitors gilteritinib and quizartinib, and the clinical-stage FLT3/IRAK4 dual inhibitor CA-4948, HPB-092 showed comparable or superior inhibitory potency against mutated forms of FLT3, improved IRAK4 inhibition, better selectivity, minimal inhibition of CYP3A4, no hERG activity, and an overall favorable safety profile, potentially benefiting a broader range of hematological malignancies. HPB-092 has received FDA clearance for a phase 1 dose-escalation and expansion study to assess its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in adult patients with relapsed or refractory AML, particularly those with FLT3 mutations and U2AF1 or SF3B1 mutations, at a leading cancer center in the US. 1https://pubmed.ncbi.nlm.nih.gov/31972687/ 2https://www.sciencedirect.com/science/article/pii/S0006497118618622 Citation Format: Suyue Wang, Lei Wu, Rui Yang, He Zhou, Bing Zhang, Wenyuan Xu, Michael Xiang, Camille Xiang, Brent Meadows, Jason Xiang. HPB-092: A novel FLT3 and IRAK4 dual inhibitor for the treatments of AML and MDS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 547.