Preclinical development of a potent dual PIM/FLT3 mutant kinase inhibitor for the treatment of AML and other hematological malignancies

Despite an evolving understanding of acute myeloid leukemia (AML), a group of heterogeneous diseases with a common feature of abnormal levels of myeloblasts in bone marrow and in circulation, the current standard of care including chemotherapy and allogeneic hematopoietic stem cell transplantation results in less than 40 % cure rate with little progress over the last decades. One of the most extensively investigated approaches in targeted therapy of AML are FLT3 inhibitors that address the population of patients harboring FLT3 mutations that result in high relapse rate and decreased overall survival when compared to patients lacking such mutations. Therefore inhibition of the constitutively active mutants of FLT3 is a promising therapeutic approach. Unfortunately, the clinical development of selective or multitargeted FLT3 inhibitors turned out to result in rapid, but very transient responses followed by disease progression. One of the main reasons for development of resistance was selection of clones harboring both ITD and tyrosine kinase mutations (TKD). In parallel, the role of PIM kinases, especially PIM1 in FLT3 mediated leukemogenesis attracted attention of the pharmaceutical industry with currently two phase I programs targeting PIM kinases in hematological malignancies. PIM kinases are important downstream effectors of FLT3 signaling and play a crucial role in cell survival and inhibition of apoptosis upon expression. For that reason, PIM kinases represent an emerging therapeutic target class in AML with promising preliminary data from clinical trials. Due to the heterogeneous nature of AML, dual inhibition of FLT3 mutant kinase and PIM kinases could lead to improved efficacy and constitute a promising approach to overcome rapid resistance development to targeted therapies. Selvita has developed a potent and selective dual PIM/FLT3 mutant kinase inhibitor - SEL24-B489 which is highly active in in vitro and in vivo AML models. The compound shows high inhibitory activity against mutated FLT3 (FLT3-ITD and TKD mutations such as D835H, D835Y, N841I) and all three PIM kinase isoforms, comparable to activity of selective inhibitors of FLT3 (A220) and PIM (AZD1208). A head to head comparison of SEL24-B489 in cellular models reveals high activity across tested cellular AML models and biomarker inhibition in line with the expected kinase activity profile. Most importantly, SEL24-B489 showed strong synergistic effect in combination with the current standard of care in AML - cytarabine, and with other targeted inhibitors in advanced clinical development. The activity of B489 in vivo in xenograft models of AML and lymphomas after oral administration was higher than compared to selective PIM inhibitor and led to remissions in certain models. SEL24-B489 is a successful example of rational drug design and is currently in preclinical development. It represents a promising therapeutic approach which addresses alternative survival pathways downstream of FLT3 in addition to the activity on resistant FLT3 mutant kinases, which hopefully will translate into improved survival of AML patients in clinical trials. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C257. Citation Format: Wojciech Czardybon, Michal Galezowski, Pawel Guzik, Magdalena Zawadzka, Renata Windak, Izabela Dolata, Magdalena Salwinska, Radoslaw Obuchowicz, Krzysztof D. Brzozka. Preclinical development of a potent dual PIM/FLT3 mutant kinase inhibitor for the treatment of AML and other hematological malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C257.