Katerina Leftheris
Visiting professor/former CSO, Stony Brook University/Vilya, Inc.
Targeting Peptides and Macrocycles as Drugs: Novel approaches on the Horizon
Abstract
There has been a significant resurgence in the advancement of peptides and macrocycles as therapeutic agents. This has been due in part to four main advances;
- Improved approaches for identifying hits (mRNA display, DEL, ML approaches)
- Discovery of novel approaches to drug delivery (permeation enhancers, sustained release formulations, etc.)
- The drug discovery of unique modalities requiring peptide/macrocycle binders such as drug conjugates and radioligand targeting agents.
- Renewed medicinal chemistry efforts targeting macrocycles/peptides
While these advances have yielded several clinical candidates, there are still significant unsolved challenges that continue to impede the overall drug discovery success rate. Often, the DMTA cycle is too long, in part due to lengthy, often challenging syntheses of peptides/macrocycle analogs off DNA. To improve cycle time, building blocks are often limited to what can be purchased, potentially limiting the diversity of structural motifs tested. The resulting hits frequently have poor ADME properties requiring an extensive medicinal chemistry effort. Also, routine delivery of bioactive peptides/macrocycles inside a cell remains a challenge. This talk will address some of these challenges and what novel approaches are currently in exploratory development. These include:
- The design of polymer-bound peptides that can penetrate a cell and show functional cellular activity as well as in vivo efficacy.
- A macrocycle-payload delivery system targeting the internalization of specific membrane bound proteins
- A machine learning engineered, nonribosomal screening approach that can generate peptides/macrocycles inside a cell
Bio
Dr. Katerina Leftheris is currently a Biotech builder and executive leader. She holds a Visiting Professorship with Stony Brook University, is currently an SAB member and holds Board of Director positions for several biotech companies focused on peptides and macrocycles. She has spent over 25 years in the small molecule/macrocycle drug discovery and early development space from early screening for hits (HTS, DEL) Ph 1 clinical studies. Throughout her career, she and her teams have put 15 compounds into the Clinic spanning many molecular targets including (but not limited to) kinases, GPCR’s, NHR’s, protease inhibitors, E3 ligase modulators/ligand directed degraders, and integrins. These targets cover debilitating diseases in several therapeutic areas including oncology, I/O, immunology, neuroscience, metabolic diseases and fibrosis.
She was most recently the CSO of Vilya Inc, an Arch Ventures-backed biotech company advancing macrocycles as oral drugs using machine learning algorithms first developed by the D. Baker Lab (U. Washington). She built out a full in-house drug discovery team and advanced several targets using ML predictive docking algorithms. Prior, she held multiple positions including SVP for Drug Discovery, Rheos Medicines and VP of Discovery Chemistry at Pliant Therapeutics, While at Pliant, she built and led discovery teams and is co-inventor of multiple integrin inhibitors in the clinic including Bexotegrast, an orally active avb6/1 inhibitor currently in PhIIb/PhIII for Idiopathic pulmonary fibrosis and primary sclerosing cholangitis.
Earlier, Katerina was site-head of Discovery Chemistry for Celgene, San Diego, where she built and led chemistry teams in advancing five novel clinical candidates, including the then nascent degrader approach utilizing glutarimide CRBN binders. Prior, she held positions of increased leadership with Vitae Pharmaceuticals . Earlier in her career, Katerina held positions of increasing responsibility in Discovery Oncology and Immunology Chemistry at Bristol-Myers Squibb.
To date, Katerina has over 140 publications/issued patents. She is an elected ACS division councilor and sits on the Executive Committee of the MEDI division of the American Chemical Society.
Katerina earned her B.A. in chemistry from Smith College, Ph.D. in organic chemistry from the University of California, San Diego and completed an NIH Postdoctoral Fellowship, University of Pennsylvania.