Hong-yu Li, Ph.D.

Professor of Pharmacology

Personal Statement:

The Li lab research has been focused on the following three aspects.

1. Drug Discovery of Targeted Therapeutics, Focusing on Single Agent Poly-pharmacology (SAP):  Drug discovery campaigns based on validated targets represent a new frontier for drug hunting. In the case of anti-cancer therapeutics, goals of targeted treatments are to provide cancer patients with agents, such as tyrosine kinase inhibitors (TKI), designed to target tumor cells or the tumor micro-environment. Unfortunately, drug resistance with single-target therapeutics invariably develops due to an inability to sustainably knock out tumor-survival pathways or to maintain activity on the target as additional mutations form. Resistance could be reduced by the simultaneous knockout of multiple pathways and/or crucial mutants. We have pioneered a new direction of medicinal chemistry by optimizing the potency in in vitro and in vivo for two or more personalized targets in a balanced fashion.  We call this drug discovery approach Synergistic Medicinal Chemistry (SMC).  A single agent with an appropriate inhibitory profile can possess the benefits of combination therapy and effectively target tumor growth while preventing resistance formation. In addition, this approach would be able to improve the potency and reduce the toxicity.

2. Drug Discovery Research for “non-druggable” targets: We have initiated drug-discovery efforts on the cPH domain, less-validated kinases (Nek2, LKB1, etc.), transcriptional factors 9 (ERG, LEF1), SETDEB1, Skp2 E3 ligase, and mutant Kras-driven phenotypic screening. Our efforts in these drug discovery areas has filled in innovational gaps left out by the pharmaceutical industry.

3. Development of fragment library and novel synthetic methodologies for accelerating the drug discovery process.

Kinase fragment libraries are traditionally composed of small hinge binders of one or two fused aryl and/or heteroaryl ring systems with hydrogen-bond donors or acceptors.  Such fragments are highly polar and can aggregate at the millimolar concentrations necessary to achieve activity in a biochemical fragment screen.  As a result, achieving a good noise to signal ratio is a major challenge with this methodology.  A kinase-directed fragment (KDF) library was designed to enhance sensitivity and more effectively interrogate binding functionalities at a kinase hinge.  This KDF library contains a diverse set of heterocyclic, hinge-region binders along with moieties that can engage lipophilic pockets or the ribose sugar pocket. Accordingly, KDFs have larger molecular weights and are generally more active than fragments contained in traditional libraries, permitting screening in the micromolar range.

Novel synthetic methodologies.  We have developed novel chemistry and synthetic methodologies that permit the facile and/or rapid generation of fragments, drug-like scaffolds, and high-value intermediates. The developed methodologies/approaches have been implemented in the generation of hits, leads, and drug candidates in a high-throughput fashion. High-throughput synthesis allows the rapid identification of clinical candidates.