The WNT genes encode a large family of cell-to-cell signaling proteins essential to embryonic development and tissue regeneration. Aberrant Wnt signaling also plays an important role in the formation and metastasis of colorectal cancer (CRC). Modulating Wnt signaling may thus help prevent cancer and facilitate tissue engineering. Our IWP and IWR molecules are the founding members of the small-molecule Wnt inhibitors. IWP inhibits the secretion of the Wnt proteins by targeting porcupine (PORCN), a membrane-bound O-acyltransferase (MBOAT) family protein. Through a series of scaffold morphing, we have generated a highly potent and stable PORCNi that can effectively shut down both canonical and noncanonical Wnt signaling. By contrast, IWR inhibits tankyrases (TNKS/2, also known as PARP5A/B or ARTD5/6), two unique members of the diphtheria toxin-like ADP-ribosyltransferase (ARTD) family proteins. By blocking the catalytic function of TNKS, it prevents the PARsylation and thus the degradation of Axin, a scaffold protein in the β-catenin destruction complex (DC). Accumulation of Axin enhances DC function and reduces soluble β-catenin. TNKSi suppresses canonical Wnt signaling mediated by β-catenin; however, it only has limited effects on tumor growth. Our current research focuses on studying how tankyrase affects DC assembly in order to overcome issues associated with TNKSi.
Small Molecule-mediated Disruption of Wnt-dependent Signal Transduction in Tissue Regeneration and Cancer
Chen, B.; Dodge, M. E.; Tang, W.; Lu, J.; Ma, Z.; Fan, C.-W.; Wei, S.; Hao, W.; Kilgore, J. A.; Williams, N. S.; Roth, M. G.; Amatruda, J. F.; Chen, C.; Lum, L.
Nat. Chem. Biol. 2009, 5, 100–107 (PMID: 19125156)
Diverse Chemical Scaffolds Support Direct Inhibition of the Membrane Bound O-Acyltransferase Porcupine
Dodge, M. E.; Moon, J.; Tuladhar, R.; Lu, J.; Jacob, L. S.; Zhang, L.-s.; Shi, H.; Wang, X.-L.; Moro, E.; Mongera, A.; Argenton, F.; Karner, C. M.; Carroll, T. J.; Chen, C.; Amatruda, J. F.; Lum, L.
J. Biol. Chem. 2012, 287, 23246–23254 (PMID: 22593577)
The Development of Highly Potent Inhibitors for Porcupine
Wang, X.-L.; Moon, J.; Dodge, M. E.; Pan, X.; Zhang, L.; Hanson, J.; Tuladhar, R.; Ma, Z.; Shi, H.; Williams, N. S.; Amatruda, J.; Carroll, T. J.; Lum, L.; Chen, C.
J. Med. Chem. 2013, 56, 2700–2704 (PMID: 23477365)
Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells
Kulak, O.; Chen, H.; Holohan, B.; Wu, X.; He, H.; Borek, D.; Otwinowski, Z.; Yamaguchi, K.; Garofalo, L. A.; Ma, Z.; Wright, W.; Chen, C.; Shay, J. W.; Zhang, X.; Lum, L.
Mol. Cell Biol. 2015, 35, 2425–2435 (PMID: 25939383)
Development of a Triazole Class of Highly Potent Porcn Inhibitors
You, L.; Zhang, C.; Yarravarapu, N.; Morlock, L.; Wang, X.-L.; Zhang, L.; Williams, N. S.; Lum, L.; Chen, C.
Bioorg. Med. Chem. Lett. 2016, 26, 5891–5895 (PMID: 27876319)
Installation of a Cancer Promoting WNT/SIX1 Signaling Axis by the Oncofusion Protein MLL-AF9
Zhang, L.-s.; Kang, X.; Lu, J.; Zhang, Y.; Wu, X.; Wu, G.; Zheng, J.; Tuladhar, R.; Shi, H.; Wang, Q.; Morlock, L.; Yao, H.; Huang, L. J.-s.; Maire, P.; Kim, J.; Williams, N.; Xu, J.; Chen, C.; Zhang, C. C.; Lum, L.
EBioMedicine 2019, 39, 145–158 (PMID: 30528456)
Stereoselective Fatty Acylation Is Essential for the Release of Lipidated WNT Proteins from the Acyltransferase Porcupine (PORCN)
Tuladhar, R.; Yarravarapu, N.; Ma, Y.; Zhang, C.; Herbert, J.; Kim, J.; Chen, C.; Lum, L.
J. Biol. Chem. 2019, 294, 6273–6282 (PMID: 30737280)