Zhi-Ping Liu Lab

In order to screen for and develop new KDM4 inhibitors that might be used in the treatment of heart disease, Our group turned to cancer cell culture models since at present there is no heart cell line that can be cultured long term.  We took advantage of the fact that KDM4B is overexpressed in many human tumors including PCa.  KDM4B is co-activator of the androgen receptor (AR) and thus known as a potential therapeutic target.  Yet to date, few KDM4 inhibitors have been developed that have anti-prostate tumor activity in vivo. In collaboration with scientists in NIH, we identified several novel inhibitors of KDM4 proteins and showed that these inhibitors blocked prostate tumor growth both in vitro and in vivo, identifying KDM4B as the relevant target (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578295/).  We went on to identify a new and novel function for KDM4B in alternative splicing of the AR and demonstrated that KDM4B acts to promote castration-resistant prostate cancer (CRPC) via this mechanism (https://pubmed.ncbi.nlm.nih.gov/31647098/). This is extremely exciting and important work. Mechanistically, we demonstrated that KDM4B can promote prostate tumorigenesis via at least three mechanisms: 1) as an AR-co-activator in the AR-signaling pathway under hormone-sensitive conditions, 2) promoting cell cycle progression as a BMYB-coactivator in the absence of the AR-signaling such as in treatment induced neuroendocrine prostate cancer, and 3) promoting CRPC via alternative splicing of AR-V7 in response to castration in AR-positive cells.  Together these findings support the concept that targeting KDM4B may be an effective therapeutic approach in a broad spectrum of PCa pathologies including both AR-dependent and AR-independent PCa.  Furthermore, we have tested one of the inhibitors, B3, in a variety of pre-clinical mouse models of PCa as either a single agent or combination therapy with current PCa drugs and observed great synergy between B3 and enzalutamide, a second-generation AR pathway inhibitor, and with the mTOR inhibitor rapamycin (https://www.researchsquare.com/article/rs-957516/v2). The synergy between KDM4B inhibitors and PCa therapeutics is clinically significant as polypharmacy and drug resistance are often observed in elderly PCa patients. A deeper mechanistic study of the synergy is underway currently in the lab.     

In an effort to translate basic scientific discovery to clinical application, we are collaborating with medicinal chemist Dr. Jung-mo Ahn at UT Dallas and PCa expert Dr. Jer-Tsong Hsieh at UTSW. We have designed and synthesized hundreds of analogs based on the lead compound B3 from the NIH library.  Through iterative lead optimization, more than 10 of these compounds have improved efficacy and selectivity in inhibiting growth of prostate tumor cells in vitro.   We have applied for patent protection of these compounds.  Three years ago, in collaboration with a like-minded colleague Dr. Elisabeth Martinez, we initiated a start-up company based on KDM inhibitors, Raphael Pharmaceuticals LLC.  We have obtained our first NCI R41 STTR (small business technology transfer) grant to develop these compounds for Prostate Cancer therapeutics.