Cambridge Healthtech Institute's Dr. Anjani Shah, Conference Director, recently spoke with Dr. Xin Huang from Amgen, about his upcoming presentation on "Structure-Based Design of Novel Inhibitors of the MCL-1’s Protein-Protein Interaction" at CHI’s Protein-Protein Interactions Conference on April 3-4, 2018 in San Diego at our www.DrugDiscoveryChemistry.com event.

How is MCL1 related to BCL2 and why is it a target of interest?

The first protein-protein interaction (PPI) inhibitor to reach the market was the BCL2-inhibitor, Venetoclax, launched in 2016 to combat chronic lymphocytic leukemia and co-developed by Abbvie and Genentech. Venetoclax disrupts the protein complex BCL2 belongs to for promoting apoptosis.

BCL2 and MCL1 are both pro-survival members of the BCL2 family and attractive targets. It’s of interest, even to Abbvie who already has a BCL2-targeted drug on the market (Venetoclax), because there are some cancers where BCL2 inhibitors don’t work due to the presence of resistant cells that overexpress MCL1.

Who else is working on MCL1 inhibitors?

We at Amgen have a compound in phase 1 clinical trials. Servier published their Mcl1 inhibitor about 1 year ago. Astra Zeneca and Abbvie are also working on MCL1 targeted compounds but the details of their compounds have not yet been disclosed.

The laboratory of Stephen Fesik from Vanderbilt University is also targeting MCL1; Dr. Fesik was the lead investigator on the BCL2 program (Venetoclax precursor) when he was at Abbott.

(CHI note: James Tarr from Fesik’s Lab will present their MCL1 work at the PPI conference; and Dr. Fesik will deliver the Plenary Keynote address about his lab’s work on ras and myc, at the overall event www.DrugDiscoveryChemistry.com event)

What aspect of your MCL1 inhibitor program will your talk focus on?

My talk will cover how we developed the MCL1 inhibitor based on crystal structures of MCL1. We will focus on structural based drug discovery (SBDD) of the inhibitor. We disclosed this clinical candidate recently, summer of 2017, but earlier talks have focused on either chemistry or biology; this will be the first presentation where SBDD is a focus.

How did you find the inhibitor?

We found the MCL1 inhibitor in a FRET assay, which is a type of high throughput screen used for PPI targets. I’ll spend a slide or two on the screen because we also used this approach to find the inhibitor of MDM2, another PPI target. The MDM2 inhibitor is now in clinical trials.

The screen provided just one hit – but that hit enabled us to obtain a co-crystal with MCL1 and solve its structure. The structural knowledge enabled us to optimize a micromolar hit into an inhibitor with 50-100picomolar affinity.

Speaker Biography:

Xin Huang, PhD, Principal Scientist, Department of Molecular Engineering, Amgen

Xin Huang, Ph.D., is Head of Structural Biology at Amgen. His group (at Cambridge, MA & South San Francisco, CA) has been working on structure-based drug discovery and development of both small and large molecules for various therapeutic areas such as oncology, inflammation, neuroscience, and metabolic disorders. Dr. Huang joined Kinetix Pharmaceutical in July 2000 and Amgen in December 2000 as a result of Amgen’s acquisition of Kinetix. Prior to pharmaceutical/biotech industry, Dr. Huang was a postdoc with Prof. Michael Eck at Dana Farber Cancer Institute and Harvard Medical School. Dr. Huang holds a Ph.D. in Chemistry from Columbia University.