ESMO Asia Congress 2022

Abstract 36P

Background

MCL-1 protein belongs to the Bcl-2 family consisting of both pro- and anti-apoptotic proteins. It serves as a master pro-survival factor by inhibiting apoptosis in a broad range of human malignancies. MCL-1 is involved in cancer resistance to different types of therapies, thus its targeting appears very attractive. Although several MCL-1 inhibitors have been studied in clinical trials, none has been approved for clinical use so far. Degradation of a target protein offers several advantages over traditional inhibitors, e.g. potential to overcome resistance to inhibitors, greater response even at a lower dose, extended pharmacodynamics, better selectivity and many others. This approach has recently emerged as a novel therapeutic modality in drug discovery. In this report, we present an in vitro and in vivo characterization of a newly-developed compound capable of degrading MCL-1.

Methods

A series of biophysical methods (FP, SPR, AlphaLisa) have been utilized to characterize compound interactions with MCL-1 protein and E3 Ligase. The biological properties of the reported molecule have been determined using cancer cell culture models (cell viability assessment using Cell Titer-Glo Assay), molecular biology techniques (western blots to confirm target protein degradation, apoptosis induction and the MoA) as well as a MV-4-11 xenograft in vivo model.

Results

The reported compound binds both E3 Ligase and target protein MCL-1 with high affinity and forms a ternary complex in vitro. In cancer cells, it induces the degradation of MCL-1 which results in apoptosis induction and cell death. The compound shows a desirable PK and PD profile, as well as causes in vivo tumor growth inhibition in a human AML MV4-11 xenograft mouse model.

Conclusions

Presented results indicate that targeting MCL-1 protein by induction of its degradation could represent a new and effective strategy for cancer treatment.