Inhibition of MCL-1 with small molecules in multiple cancers
A synthetic small molecule targeting MCL-1 in breast and non-small cell lung cancer carcinomas has been developed at McGill University.
During cancer progression, the loss of apoptosis regulation is often required and serves as a major barrier to effective treatment. Evidence suggests apoptotic signaling is disrupted in all human cancers, either by mutations of core apoptotic machinery or by other mechanisms. One of the anti-apoptotic proteins that is essential to cancer cell survival and homeostasis is Myeloid cell leukemia-1 (MCL-1). MCL-1 overexpression is observed in many human malignancies and is often associated with a poor prognosis because of drug resistance.
As a synthetic small-molecule antagonist of MCL-1 activity, this invention is cytotoxic to human myeloid leukemia cells at micromolar concentrations but is non-toxic to healthy cells at pharmacologically relevant doses. Not only can this agent treat distinct cancer types while potentially avoiding unwanted side effects, but it could also be a good combination therapy since it sensitizes lymphoma tumor xenografts to the chemotherapy molecule doxorubicin in an isogenic mouse model. This invention has application as a treatment for human breast and non-small cell lung cancer carcinomas, where MCL-1 overexpression is required for disease maintenance.
- Can treat distinct cancer types with MCL-1 overexpression and be used in combination therapy to sensitize tumors to other chemotherapy drugs
- Non-toxic to healthy cells at pharmacologically relevant doses