Bcl-2 / Bcl-xL / Mcl-1 inhibitors
Target and Target Class: B-cell lymphoma-2 and xL (Bcl-2 / Bcl-xL), Myeloid cell leukemia-1 (Mcl-1); Protein-Protein interaction
Indication: Oncology
Rationale
Inhibition of Bcl-2 and Bcl-xL is predicted to result in a promotion of the apoptosis of tumor cells which frequently produce these two anti-apoptosis factors at increased levels. Inhibition is expected to shift the apoptotic cell balance towards cell death and thus slowing disease progression and potentiating the chemo-efficacy of available chemotherapeutics. The Mcl-1 protein is a highly regulated and short-lived anti-apoptotic member of the Bcl-2 family. It is more distantly related to Bcl-2 compared to e.g. Bcl-xL and Bcl-w. Mcl-1 was only recently recognized as a putative resistance factor for single-agent efficacy of the Abbott Laboratories ABT-737 series of Bcl-2 family inhibitors towards many tumors. Inhibition of Mcl-1, or its upstream regulation, is hypothesized to be synergistic with Bcl-2 / Bcl-xL inhibition. Inhibition of Bcl-2 family members is therefore of interest for the treatment of various tumor types, including haematological malignancies and solid tumors like small cell lung and prostate cancers.
Status
Evotec has identified active Bcl-2, Bcl-xL and Mcl-1 inhibitors following a fragment-based screen and is currently optimizing these inhibitors.
