Our research is at the emerging interface of chemistry and biology by using chemical tools to dissect the signaling pathways implicated in cancer development and maintenance. A particular focus in the lab is to develop chemical tools and potential cancer therapeutics for targets that are not well understood. Synopses of two ongoing projects are listed below:
Chemical inhibitors of CREB-mediated gene transcription
cAMP-response element binding protein (CREB) is a nuclear transcription factor. Its transcription activity is regulated by dynamic phosphorylation and dephosphorylation events. CREB is a signaling hub of many signaling transduction pathways that are often dysregulated in cancer cells. In cancer cells, CREB is often overexpressed and/or overactivated. Functional genetics studies demonstrated that intact CREB's transcription activity is critical in maintaining cancer phenotype. We hypothesized that small molecule inhibitors of CREB would represent potential novel cancer therapeutics against multiple types of cancers. To test this hypothesis, we initiated a research program to identify small molecule inhibitors of CREB-mediated gene transcription. Among these inhibitors, we invented 666-15 as a very potent and cell-permeable CREB inhibitor. 666-15 not only inhibited cancer cell growth, but also showed robust in vivo anticancer activity.
Chemical tools to modulate nuclear lamin functions
Nuclear lamins (LMNA, LMNB1, LMNB2 and LMNC) are type V intermediate filaments. They form nuclear lamina underneath inner nuclear membrane. These proteins are highly homologous to each other and organized into 3 major domains: a non-helical head domain, a coiled-coil rod domain and an Ig domain at the C-terminal end. In addition to their structural roles to support the nuclear shape, they also present signaling functions through poorly understood mechanisms. For example, HGPS (Hutchinson-Gilford progeria syndrome) is caused by a point mutation in LMNA gene to activate a cryptic splicing site leading to premature aging. This mutant LMNA is hypothesized to disrupt the normal signaling function of wild type LMNA. Elucidation of lamins' signaling mechanisms has been hampered by the lack of a chemical tool to directly modulate lamins. We are utilizing reverse and forward chemical genetics strategies to identify small molecule modulators of lamins. These compounds will provide critical tools to further our understanding of lamins' signaling functions. They will also provide starting points for developing potential therapeutics for aging and cancer.