CSB Joint Appointed Faculty
Joseph K. Agyin, Ph.D.Assistant Professor/Research
Purdue University, 1996
Dr. Agyin joined the Department of Cellular & Structural Biology in September 2002. Prior to he was at the Cancer Therapy and Research Center's Institute for Drug Development, where he started as a Postdoctoral Research Fellow in 1996 and was later promoted to Assistant Member. Dr. Agyin is a recipient f an AACR Minority-Serving Institution faculty Scholar Award (2006), and an AACR Minority Scholar Award (2005).
The main interest of my laboratory is the design and synthesis of small molecules for drug discovery purposes. Our current research focus is on the development of bone-targeted drugs as potential treatments for multiple myeloma and its associated bone disease. The three projects we are currently pursuing are on proteasome inhibitors, 2-methoxyestradiol analogs, and bone-targeted nitric oxide donors.
PROTEASOME INHIBITORS: Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Our research focus is on the development of novel and innovative therapies aimed at selectively delivering therapeutic agents to the bone microenvironment. The proteasome inhibitor Bortezomib (aslo known as Velcade or PS341) is currently in clinical use for patients with advanced or refractory MM. We are currently working on the synthesis of Velcade-bisphosphonate conjugates to selectively target the proteasome inhibitor to bone for effective treatment of myeloma. My group has recently synthesized an analog of Velcade that shows promising anti-myeloma effect. We have also synthesized bone-targeted nanoparticles loaded with velcade. Biological studies of these compounds are currently ongoing.
2-METHOXYESTRADIOL: Another agent we are currently studying is 2-methoxyestradiol (2-ME). 2-ME is an endogenous metabolite of estradiol with very good activity against MM and other cancer cell lines. We have synthesized 2-ME-bisphosphonate conjugates and shown that these compounds can effectively kill myeloma cells both in vitro and in vivo. These studies are currently ongoing.
NITRIC OXIDE DONOR-BISPHOSPHONATE CONJUGATES: We are also interested in the use of nitric oxide (NO) donors as bone anabolic agents. Bisphosphonates (BPs), which have a great affinity for bone, are effective inhibitors of osteoclastic bone resorption and prevent osteoporotic fractures, but they do not stimulate bone formation or replace bone that has been lost. There is a growing body of evidence from experimental and clinical studies suggesting that NO plays an important role in the regulation of bone remodeling, and that NO donors have stimulatory effects on bone mass in rats and humans. Our group has designed and synthesized a series of NO donor-bisphosphonate (NO-BP) conjugates based on the rationale of using the high affinity of BPs for bone mineral to target and localize both NO and the BP to the bone microenvironment, thereby superimposing the bone anabolic effect of NO on the anti-resorptive effect of BPs in the treatment of osteoporosis and tumor-induced osteolysis. We have shown, in organ cultures of neonatal murine calvaria and in vivo in rats, that the NO-BP conjugates stimulate bone formation and alkaline phosphatase activity in addition to inhibiting bone resorption.
Nuclear Magnetic Resonance
Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, Cornell JE, Pollock BH, Mundy GR, Sun LZ. (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Res. 2006 Jul 1;66(13):6714-21.
Timothy A. Waugh, Joseph K. Agyin, John J. Nash, and Harry Morrison, "Steric Effects on the C6-C1-C2 Valence angle in exo-6-chloronorbornenes: implications for orbital coupling", Tetrahedron Letters, 40, 6717-6720 (1999).
Plummer, B. F., Faiz, S., Wiederhold, T., Wooten, M., Agyin, J., Krause, K. L., Miller, M. D. Stereochemical -facial selectivity of the Diels-Alder reaction of benz[a]aceanthrylene and 1,4-diphenylbenz[a]aceanthrylene. J Org Chem 62:9290-9292, (1997).
Agyin, J. K., and Morrison, H. Steroids as photonic wires. Olefin photoisomerization involving ketone singlet-triplet switches by through-bond energy transfer. J Am Chem Soc 119:7945-7953, (1997).
Agyin, J. K., Morrison, H., and Siemiarczuk, A. Antenna-initiated photochemistry of distal groups in trifunctional steroids. Olefin photoisomerization involving ketone S-T switches by through-bond energy transfer. J Am Chem Soc 117:3875, (1995).