Nuclear Receptor Biology & Drug Discovery
(Professor Yong Eu Leong)
Our Laboratory focusses on androgen and estrogen ligand-receptor biology. Our team have the rare capability to develop new drugs from bioactive compound discovery, to proof of concept in animal models, to completion of phase 1 and 2 randomised control trials in humans.
Studies on the androgen receptor gave insights on the molecular mechanisms whereby mutations and polymorphisms result in androgen insensitivity syndromes on one hand, and androgen excess prostate cancer on the other(1). Of note our lab discovered the causative relationship between polymorphisms of androgen receptor to ambiguous genitalia (2), male infertility, low sperm counts (3) and devised pharmacological therapy resulting in restoration of fertility and successful pregnancy(4).
Studies on the estrogen receptor has enabled screening of bioactive compounds from Traditional Chinese Medicines for post-menopausal bone health(5). We isolated, characterized, and patented novel compounds that activate estrogen and other TRAF-6 signaling pathways to improve osteoblast and osteoclast cellular function(6). These compounds and their parent extracts have shown potential utility in menopause, bone health, metabolic disease, breast and prostate cancers.
This effort has resulted in 5 patent applications, three of which have been granted and commercialized. Based on our patent, NUS Industry Liaison Office officially signed a Research Collaboration Agreement with Schwabe pharmaceuticals GmbH & Co. KG, of Germany to develop pharmaceutical products from plants of genus Epimedium(7). We have completed the necessary pre-clinical pharmacokinetic and pharmacodynamic studies in animal models to meet Singapore Health Sciences Authority regulatory requirements for human trials(5). We have completed Phase 1 pharmacokinetic studies in humans(8) and are completing a phase 2 randomised control trial of the use of Epimedium drug for post-menopausal osteoporosis.
Achievement of these planned Phase1/2 human studies will result in pharmaceutical-quality botanical drugs discovered and made in Singapore.
Publications
- Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997;82(11):3777-3782. doi:10.1210/jcem.82.11.4385.
- Ong YC, Wong HB, Adaikan G, Yong EL. Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutation. Lancet. 1999;354(9188):1444-1445. doi:10.1016/s0140-6736(99)03205-5
- Ghadessy FJ, Lim J, Abdullah AA, et al. Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions. J Clin Invest. 1999;103(11):1517-1525. doi:10.1172/JCI4289
- Yong EL, Ng SC, Roy AC, Yun G, Ratnam SS. Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene. Lancet. 1994;344(8925):826-827.
- Indran IR, Liang RL, Min TE, Yong EL. Preclinical studies and clinical evaluation of compounds from the genus Epimedium for osteoporosis and bone health. Pharmacol Ther. 2016;162:188-205. doi:10.1016/j.pharmthera.2016.01.015.
- Tan EM, Li L, Indran IR, Chew N, Yong EL. TRAF6 Mediates Suppression of Osteoclastogenesis and Prevention of Ovariectomy-Induced Bone Loss by a Novel Prenylflavonoid. J Bone Miner Res. 2017;32(4):846-860. doi:10.1002/jbmr.3031.
- Yap SP, Shen P, Butler MS, Gong Y, Loy CJ, Yong EL. New estrogenic prenylflavone from Epimedium brevicornum inhibits the growth of breast cancer cells. Planta Med. 2005;71(2):114-119. doi:10.1055/s-2005-837776.
- Teo YL, Cheong WF, Cazenave-Gassiot A, et al. Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans. Planta Med. 2019;85(4):347-355. doi:10.1055/a-0806-7673.