The cellular responses controlled by the secreted Wnt proteins are essential to almost all aspects of embryogenesis. In developed tissue, genetic and molecular alterations that give rise to misactivation of these signaling processes frequently drive cancerous cell growth. We have identified two distinct chemical strategies to disable Wnt-mediated signaling from screening a large synthetic chemical library in cultured cells. Whereas one compound class targets an acyltransferase essential for the production of Wnt molecules, another class promotes the destruction of a linchpin transcriptional co- activator. The cell growth inhibitory effect of disabling Wnt-mediated signaling in certain cancerous contexts is well established. Yet, the ability of chemically based strategies to achieve similar effects is largely untested. The studies in this proposal will interrogate Wnt-mediated signaling at the molecular, cellular, and organismal level using new chemical biology-based tools, and establish a framework for the deployment of Wnt inhibitors in cancerous contexts. In particular, we focus on lung cancer given the dependence of this disease on both targets of our compound portfolio. These studies should facilitate a transition from front-line anti-cancer agents that are generally toxic to rapidly diving cells to those that are tailored to the underlying genetics of individual cancers.
Deviant activation of cellular responses controlled by the Wnt family of secreted molecules is common in cancerous cells. Our study will delineate novel mechanisms of Wnt-mediated signaling using new chemically based strategies, and evaluate the effectiveness of two novel classes of small molecules that target Wnt-mediated signal transduction for inhibiting tumor initiation and progression.
|Zhang, Li-Shu; Lum, Lawrence (2018) Chemical Modulation of WNT Signaling in Cancer. Prog Mol Biol Transl Sci 153:245-269|
|Fan, Chen; Yarravarapu, Nageswari; Chen, Hua et al. (2018) Regulation of tankyrase activity by a catalytic domain dimer interface. Biochem Biophys Res Commun 503:1780-1785|
|Fan, C-W; Yarravarapu, N; Shi, H et al. (2018) A synthetic combinatorial approach to disabling deviant Hedgehog signaling. Sci Rep 8:1133|
|Moon, Jesung; Zhou, Huanyu; Zhang, Li-Shu et al. (2017) Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist. Proc Natl Acad Sci U S A 114:1649-1654|
|Wu, Xiaofeng; Zhang, Li-Shu; Toombs, Jason et al. (2017) Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor. Nat Cell Biol 19:1226-1236|
|Zhang, Li-Shu; Lum, Lawrence (2016) Delivery of the Porcupine Inhibitor WNT974 in Mice. Methods Mol Biol 1481:111-7|
|You, Lin; Zhang, Chengwei; Yarravarapu, Nageswari et al. (2016) Development of a triazole class of highly potent Porcn inhibitors. Bioorg Med Chem Lett 26:5891-5895|
|Tuladhar, Rubina; Yarravarapu, Nageswari; Lum, Lawrence (2016) Monitoring Wnt Protein Acylation Using an In Vitro Cyclo-Addition Reaction. Methods Mol Biol 1481:11-6|
|Kulak, Ozlem; Chen, Hua; Holohan, Brody et al. (2015) Disruption of Wnt/?-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells. Mol Cell Biol 35:2425-35|
|Tuladhar, Rubina; Lum, Lawrence (2015) Fatty acyl donor selectivity in membrane bound O-acyltransferases and communal cell fate decision-making. Biochem Soc Trans 43:235-9|
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