Dr. Juswinder Singh is a world-renowned computational chemist and structure-based small molecule drug designer, developing methods that have been successfully applied in the discovery of multiple NCE’s, several of which are now in clinical development.
Prior to funding Avila, Dr. Singh led computational chemistry efforts at Biogen Idec where he was most recently Director of Structural Informatics, and he also pioneered the development of novel approaches in the computational chemistry and cheminformatics at Parke-Davis. Dr. Singh received his PhD in rational drug design at the University of London followed by a post-doctoral fellowship at University College London.
His first lecture presented on Thursday May 10th 2018 was titled:
“The Resurgence of Covalent Drugs”
Covalent drugs have proven to be safe and successful therapies for a wide variety of indications for more than a century. Despite this there has been disconnect between their importance and their systemic investigation due to perceived safety risks. In addition, most of these drugs were discovered through serendipity and few methods had been developed to discover them rationally. Covalent drugs offer pharmacological advantages over their reversible counterparts which can lead to unique therapeutic profiles leading to novel breakthrough medicines. Recently, there has been much interest in the development of targeted covalent inhibitors (TCIs) which use computer-assisted computational chemistry methodology and structural bioinformatics for their discovery. I will highlight the TCI strategy and also the breadth of the opportunity which we term the “covalent druggable proteome”. I will describe the remarkable clinical impact of TCIs in the treatment of EGFR driven lung cancers with the drug Rociletinib which has received breakthrough status from the FDA. This covalent inhibitor is able to recognize the mutant form of the oncogenic kinase while sparing the WT form of the enzyme leading to greater efficacy without the dose-limiting toxicities seen for the first and second-generation EGFR kinase inhibitors. I will describe the discovery and development of the targeted covalent drugs but also unique learnings from the clinical development that have provided key insights into tumor biology and drug resistance. We are witnessing a resurgence in the area of covalent drugs which have the potential to add an important class of breakthrough medicines to our armamentarium.
His first lecture presented on Friday May 11th 2018 was titled:
“A revolutionary approach to the treatment of chronic lymphocytic leukemia with covalent drugs”
Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton’s tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.