Abstract 5394: First-in-class dual PIM/FLT3 kinase inhibitor SEL24-B489 for the treatment of hematological malignancies

Abstract

Abstract Despite huge effort spent on understanding acute myeloid leukemia (AML), current standards of care are still based on the same chemotherapy agents as two decades ago - typically based on cytarabine chemotherapy with an anthracycline. Although patients aged <60 years may achieve remission to induction therapy, most patients will relapse. One of primary reasons for that is high heterogeneity of the disease. Recently one of the most extensively investigated approaches to the treatment of AML, are targeted therapies, especially inhibition of certain kinases. Probably mostly investigated up to date are inhibitors of FLT3 with most advanced clinical compound - AC220 (Quizartinib). FLT3 inhibitors are very effective in killing cancer lines with a major drawback of the therapy being fast development of resistance. PIM kinases are expressed in various cancers including AML but also other liquid tumors as well as in some solid tumors. Inhibition of PIM kinases which are downstream in the FLT3 signaling cascade have already shown influence on cancer cell survival. In addition there are great hopes related to the fact that PIM kinases were shown to contribute in resistance to FLT3 inhibitors. This leads to the conclusion that combined inhibition of PIM and FLT3 may be a rational strategy. Selvita has developed series of inhibitors combining activity against PIM and FLT3 kinases. Selected clinical candidate SEL24-B489 - has shown excellent anticancer efficacy. It is active against broad panel of AML cell lines and primary blasts, but also against other hematological cancers: DLBCL, CLL, HL - both in vitro on cell lines, patient samples and in vivo. Head to head comparison of SEL24-B489 with PIM (AZD1208) and FLT3 (AC220) inhibitors currently in clinical development will be presented. Comparison shows strong activity of SEL24-B489 against broader panel of cell lines in vitro and in vivo (in xenograft models) than AZD1208 or AC220. SEL24-B489 is currently in preclinical development and details of toxicology profile will also be discussed. Citation Format: Krzysztof Brzózka, Wojciech Czardybon, Aniela Gołas, Renata Windak, Michał Gałęzowski, Ewelina Gabor-Worwa, Bożena Winnik, Agnieszka Przybyłowicz, Maciej Szydłowski, Emilia Białopiotrowicz, Tomasz Sewastianik, Elżbieta Mądro, Ewa Lech-Marańda, Krzysztof Warzocha, Przemysław Juszczyński. First-in-class dual PIM/FLT3 kinase inhibitor SEL24-B489 for the treatment of hematological malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2015-5394