36P - Preclinical evaluation of novel MCL-1 degrader in in vitro and in vivo cancer models

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Captor Therapeutics Inc.

Funding

Captor Therapeutics Inc.

Disclosure

All authors have declared no conflicts of interest.