Deciphering the Therapeutic Potential of AMG 176: Targeting Mcl-1 in Cancer

The ability of cancers to evade apoptosis is a significant factor in their progression, with the Bcl-2 family proteins being key regulators of apoptosis. Inhibiting pro-survival Bcl-2 family members like Mcl-1 with small molecules is a promising therapeutic strategy. AMG 176, a potent and selective Mcl-1 inhibitor, is under Phase I clinical development and has been evaluated for its activity in both in vitro and in vivo settings.

AMG 176 shows high affinity and selectivity for the BH3-binding groove of Mcl-1, disrupting the Mcl-1 and Bak interaction and activating the intrinsic apoptosis pathway. This leads to an increase in caspase activity, impacting cell viability. In mice with OPM-2 multiple myeloma xenografts, oral dosing of AMG 176 resulted in a dose-dependent increase in activated Bak, with a clear relationship between pharmacokinetics/pharmacodynamics and dosing.

Different dosing regimens of AMG 176 were tested in established OPM2 xenografts, demonstrating significant tumor growth inhibition and complete tumor regression at higher doses. The efficacy was observed at doses that also induced apoptotic markers. Treatment with Compound A, a structural analog of AMG 176, resulted in a dose- and time-dependent increase in Mcl-1 protein levels, suggesting an increase in protein half-life due to the disruption of proteasome-mediated degradation.

Compound A induced rapid apoptosis and loss of viability in Mcl-1 dependent cancer cell lines, with as little as two hours of treatment being sufficient for complete cell killing in highly Mcl-1 dependent lines. Cell line profiling studies identified effects on cell viability in certain solid tumor cell lines and those of hematological origin, including multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma. An inverse correlation was found between BCLxL expression and sensitivity to Mcl-1 inhibition. Combination screens with Compound A showed synergistic effects when combined with MAPK pathway inhibitors, standard chemotherapeutics, and agents targeting additional pro-survival BCL-2 family members.

In conclusion, AMG 176 demonstrates significant in vitro and in vivo activity in Mcl-1 dependent cancer models, representing a promising therapeutic agent.

The research was presented by Sean R. Caenepeel and colleagues at the American Association for Cancer Research Annual Meeting in 2017.