Hong-yu Li , Ph.D.

Department of Pharmaceutical Sciences

Education & Training

The University of Tokyo, Tokyo, Japan, Ph.D.
Columbia University, New York, NY , Postdoc
Harvard University, Cambridge, MA, Postdoc

Teaching Responsibilities

Practice in Drug Discovery and Development for Graduate Students, course coordinator, PSGP 6114.
Medicinal Chemistry for Pharm.D. students, PhSci 4254.

Research & Scholarly Interests

• 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 the last five years, we were able to discover and develop multiple advanced kinase inhibitors with a balanced inhibitory profile through the SMC principle into the preclinical studies for IND filing.
  a. Frett, B., Carlomagno, F., Moccia, L., Brescia, A., Federico, G., De Falco, V., Admire, B., Chen, Z., Qi, W., Santoro, M., Li, H. (2015). Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology. Angew Chem Int Ed Engl, 54(30), 8717-8721. PMCID: PMC4535927.
  b. Frett, B., McConnell, N., Smith, C., Wang Y., Shah, N.P., Li, H. (2015). Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors. Eur J Med Chem, 94, 123-131. PMCID: PMC4666306.
  c. Frett, B., Moccia, M., Carlomagno, F., Santoro, M., Li, H. (2014). Identification of two novel RET kinase inhibitors through MCR-based drug discovery: design, synthesis and evaluation. Eur J Med Chem, 86, 714-723. PMCID: PMC4666024.
  d. Frett, B., McConnell, N., Wang, Y., Xu, Z., Ambrose, A., Li, H. (2014). Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies. Medchemcomm, 5(10), 1507-1514. PMCID: PMC4734651.

• Drug Discovery Research for “non-druggable” targets: We have initiated drug-discovery efforts on the cPH domain, less-validated kinases (Nek2, LKB1, etc.), 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.
  a. Frett, B., Brown, R.V., Ma, M., Hu, W., Han, H., Li, H. (2014). Therapeutic melting pot of never in mitosis gene a related kinase 2 (Nek2): a perspective on Nek2 as an oncology target and recent advancements in Nek2 small molecule inhibition. J Med Chem, 57(14), 5835-5844. PMCID: PMC4666018.
  b. Frett, B., Wang, Y., Li, H. (2013). Targeting the K-Ras/PDEδ protein–protein interaction: the solution for Ras-driven cancers or just another therapeutic mirage? ChemMedChem, 8(10), 1620-1622. PMCID: PMC4666017.
  c. Wang, Y., Kaiser C., Frett B., Li, H. (2013). Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators. J Med Chem, 56(13), 5219-5230. PMCID: PMC4666308.
  d. Lee, S., Li, C., Jin, G., Cai, Z., Han, F., Chan, C., Yang, W., Li, B., Rezaeian, A. H., Li, H., Huang, H., Lin, H.K. (2015). Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell, 57(6), 1022-1033. PMID: 25728766.

• Development of a kinase fragment library and novel synthetic methodologies for accelerating the drug discovery process.
  Kinase fragment library. 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. Two clinical candidates were developed from the KDF screens.
  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.
  a. Wang, Y., Frett, B., McConnell, N., Li, H. (2015). Metal-free, efficient hydrazination of imidazo[1,2-a]pyridine with diethyl azodicarboxylate in neutral media. Org Biomol Chem, 13(10), 2958-2964. PMCID: PMC4675458.
  b. Wang, Y., Frett, B., Li, H. (2014). Efficient access to 2,3-diarylimidazo[1,2-a]pyridines via a one-pot, ligand-free, palladium-catalyzed three-component reaction under microwave irradiation. Org Lett, 16(11), 3016–3019. PMCID: PMC4059256.
  c. Li, F., Frett, B., Li, H. (2014). Selective Reduction of Halogenated Nitroarenes with Hydrazine Hydrate in the Presence of Pd/C. Synlett, 25(10), 1403–1408. PMCID: PMC4734645.
  d. Wang, Y., Saha, B., Li, F., Frett, B., Li, H. (2014). An expeditious approach to access 2-arylimidazo [1,2-a]pyridin-3-ol from 2-amino pyridine through a novel Petasis based cascade reaction. Tetrahedron Letters, 55, 1281–1284.

Honors & Awards

• Arkansas Research Alliance Scholar
• Helen Adams & Arkansas Research Alliance Endowed Chair in Drug Discovery
• Associate Editor, Molecular Diversity
• Faculty Award of Excellence (College of Pharmacy, the University of Arizona, 2013)
• Selected as a potential Lilly’s future leader (2007 Eli Lilly HR Succession Plan)
• Recognition-Grant-Program Award (Eli Lilly & Company, 2006)
• Selected as a potential Lilly’s future leader (2005 Eli Lilly HR Succession Plan)
• Exemplary Performance Award (Eli Lilly & Company, 2005)
• Exemplary Performance Award (Eli Lilly & Company, 2004)
• The Japanese Ministry of Education, Science, Sport, and Culture Encouragement of Young Scientists Award 1996, Japan
• Naito Foundation Scholarship Achievement Award, 1995, Japan
• Graduate Fellowship, The Ichiro Kanehara Memorial Foundation,1994, Japan
• Graduate Fellowship award, The Japanese Educational Bereau,1993, Japan
• Co-founder for Synactix and Promutech Pharmaceuticals

Memberships

• American Chemical Society
• American Association for Cancer Research

Publications

• Frett, B., Carlomagno, F., Moccia, L., Brescia, A., Federico, G., De Falco, V., Admire, B., Chen, Z., Qi, W., Santoro, M., Li, H. (2015). Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology. Angew Chem Int Ed Engl, 54(30), 8717-8721. PMCID: PMC4535927.
• Frett, B., Brown, R.V., Ma, M., Hu, W., Han, H., Li, H. (2014). Therapeutic melting pot of never in mitosis gene a related kinase 2 (Nek2): a perspective on Nek2 as an oncology target and recent advancements in Nek2 small molecule inhibition. J Med Chem, 57(14), 5835-5844. PMCID: PMC4666018.
• Wang, Y., Kaiser C., Frett B., Li, H. (2013). Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators. J Med Chem, 56(13), 5219-5230. PMCID: PMC4666308.
• Lee, S., Li, C., Jin, G., Cai, Z., Han, F., Chan, C., Yang, W., Li, B., Rezaeian, A. H., Li, H., Huang, H., Lin, H.K. (2015). Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell, 57(6), 1022-1033. PMID: 25728766.
• Wang, Y., Frett, B., Li, H. (2014). Efficient access to 2,3-diarylimidazo[1,2-a]pyridines via a one-pot, ligand-free, palladium-catalyzed three-component reaction under microwave irradiation. Org Lett, 16(11), 3016–3019. PMCID: PMC4059256.

Poster: Translational Drug Development: Research that Takes you From Bench to Bedside and Beyond