Journal article

Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia

Donia M Moujalled, Giovanna Pomilio, Corina Ghiurau, Adam Ivey, Jessica Salmon, Sewa Rijal, Sarah Macraild, Lan Zhang, Tse-Chieh Teh, Ing-Soo Tiong, Ping Lan, Maia Chanrion, Audrey Claperon, Francesca Rocchetti, Adrien Zichi, Laurence Kraus-Berthier, Youzhen Wang, Ensar Hamovic, Erick Morris, Frederic Colland Show all

LEUKEMIA | NATURE PUBLISHING GROUP | 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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