Journal article
Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia
DM Moujalled, G Pomilio, C Ghiurau, A Ivey, J Salmon, S Rijal, S Macraild, L Zhang, TC Teh, IS Tiong, P Lan, M Chanrion, A Claperon, F Rocchetti, A Zichi, L Kraus-Berthier, Y Wang, E Halilovic, E Morris, F Colland Show all
Leukemia | Published : 2019
Abstract
Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spec..
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Funding Acknowledgements
We acknowledge research funding from National Health and Medical Research Council, Victorian Cancer Agency, Leukaemia Foundation of Australia, Leukemia and Lymphoma Society, Australian Cancer Research Foundation, Monash Partners, the Alfred Foundation and the Medical Research Future Fund. This work has received funding support from Servier.