CDK9 specific inhibition with AZD4573 impairs cancer-promoting gene expression such as MCL-1 and has been proven effective in hematological malignancies preclinical models.
To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-X<sub>L</sub> (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines.
Furthermore, seminal research by Servier has demonstrated for the first time that MCL-1 inhibition is tolerable in animal models of cancer, paving the way for the six Phase 1 clinical trials that are currently underway for hematological malignancies, among other cancers.
Amplification and overexpression of the myeloid cell leukemia differentiation protein MCL1 and the murine double minute protein MDM2 have been reported in various human tumors as well as hematological malignancies including acute myeloid leukemia (AML).
SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies.
Caenepeel and colleagues and Ramsey and colleagues have developed two novel, potent, and selective MCL1 inhibitors that are effective against many hematologic malignancies, and Nangia and colleagues describe how one of these inhibitors can be successfully combined with BCL-xL and MEK inhibition to treat KRAS-mutated lung cancer.<i>See related article by Ramsey et al., p. 1566</i>.<i>See related article by Caenepeel et al., p. 1582</i>.<i>See related article by Nangia et al., p. 1598</i>.
The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib.