Hong-yu Li, PhD
The ultimate goal for research projects in the Li Lab is to develop novel oncology therapeutics for the medically under-served. To accomplish this, we actively pursue a variety of kinase targets involved in cancer pathology and modulate their oncogenic signaling through small molecule inhibition. We design, synthesize, and develop all promising small molecules through a variety of novel approaches. Currently, we have an inhibitor of the RET (REarranged during Transfection) kinase in late stage pre-clinical development for the treatment of medullary thyroid cancer (MTC). The inhibitor is displaying much promise for efficacy in the clinic and has been designed to attenuate problems associated with previous MTC therapies.
Presently, we have developed numerous small molecule inhibitors for a variety of kinase related oncology targets. Research in the lab is directed at developing the small molecules pre-clinically, filing for IND (investigative new drug) status with the FDA, and pushing the therapies into clinical trials. We are a unique lab in which our ultimate goal is clinical trial entry and high-quality publications.
1) Hit generation: Utilization of a fragment-based library front-loaded with drug-like properties
The preclinical drug discovery and development pipeline has four main parts: (1) Target, (2) Hit, (3) Lead, and (4) Lead development and optimzation. The most important facet to the process is target choice, as the success of the entire process rests on a good, druggable target. However, after a good target has been identified, generating active hits to modulate the target’s function is a difficult task. In the Li Lab, we have developed a novel fragment library we utilize to quickly identify active compounds and streamline hit to lead generation. We utilized our fragment-library to quickly identify our RET inhibitor, which is our most advanced compound in late stage pre-clinical development. Additions to our fragment-library are on-going and we frequently apply this technology to rapidly uncover novel kinase inhibitor scaffolds for oncology related targets.
2) Small molecule generation, synthesis is the heart of medicinal chemistry
Synthesis is an enormous and integral part to medicinal chemistry. As a medicinal chemist, we are free to synthesize any compound we can imagine and are not bound by limits of commercial availability. In the Li Lab, we generate a variety of structurally unique analogues using available and developed synthetic methodologies. This allows us to reach novel “molecular space” and develop new chemotypes to effectively probe tumor biology.
3) Formulations and drug delivery methods
A very important aspect to drug discovery and development that is often discussed to late is the solubility of a drug in an aqueous medium. In general, small molecule inhibitors are greasy and hate aqueous solutions. In our lab, we activity develop novel formulations that help solubilize our organic inhibitors in an aqueous medium. To accomplish this, we frequently take a suspension approach, in which the organic drug is uniformly suspended in solution. We also actively pursue formulations involving nano-particles for enhanced bioavailability and drug delivery. Along side formulation work, we also design compounds that contain strategically placed metabolically activated groups, which are masked until bioactivation occurs. We are implementing this technology in the development of topical mTOR inhibitors for chemoprevention of skin cancer. The mTOR inhibitors are designed to easily pass through the membrane during topical administration; however, once absorbed, the inhibitors under go metabolic transformation that "locks" the inhibitor in the cell, enhancing chemopreventive efficacy.
- Sharma and H.Y. Li, A Regioselective, General and High Yielding method for Formaldehyde Inculsion in the 3CC Groebke-Blackburn Reaction: One Step Access to 2-Aminoimidazoazines. Synlett. (2011) 1407-1412.
- H. Y. Li,W. T. McMillen, C. R. Heap, D. J. McCann, L. Yan, R. M. Campbell,S. R. Mundla, C.-H. R. King, E. A. Dierks, B. D. Anderson, K. S. Britt, K. L. Huss, M. D. Voss, Y. Wang, D. K. Clawson, J. M. Yingling, J. S. Sawyer. Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor b Receptor Type I inhibitor as Antitumor Agent, J. Med. Chem. (2008) 51, 2302-2306.
- H.Y. Li,Y. Wang,W. T. McMillen, A. Chatterjee, J. E. Toth, S. R. Mundla,M. Voss, R. D. Boyer, J. S. Sawyer. A Concise Synthesis of Quinazolinone TGF-b RI Inhibitor Through One-pot Three-Component Suzuk-Miyaura/etherification and Imidate-amide Rearrangement Reactions, Tetrahedron (2007) 63, 11763-11770.
- H.Y. Li, Y. Wang, C.R. Heap, C.R. King, S.R. Mundla, M. Voss, D.K. Clawson, L. Yan, R.M. Campbell, B.D.Anderson, J.R. Wanger, K. Britt, K.X. Lu, W.T. McMillen, J.M. Yingling . Dehydropyrrolopyrazole transforming growth factor-β type I receptor kinase domin inhibitors: A novel benzimidazole series with selectivity versus transforming growth factor β type II receptor kinase and mixed lineage kinase-7, J. Med. Chem. (2006) 49, 2138-2143.