G007-LK [4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile] is a potent, “rule of 5” compliant and a metabolically stable Tankyrases 1 and 2 (TNKS1/2) inhibitor.
G007-LK displayed high selectivity toward TNKS1/2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. G007-LK shows a favorable combination of high target specificity to TNKS1/2, high potency, and in vitro as well as in vivo stability [1].
Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that ß-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/ß-catenin signaling and cell proliferation in intestinal crypts [2].
The biggest challenge to further development of G007-LK is its tolerability profile. In healthy mice, the compound blocked the regeneration of intestinal crypt cells, a normal process that depends on WNT signaling. Tankyrase inhibitors do not directly kill tumors but instead appear to block the self-renewal of undifferentiated cells with stem cell–like properties that are thought to be the source of colorectal tumors. Blocking tankyrases appears to drive those cells into a more differentiated state, thus reducing the supply of cancer stem cells.
Wnt Signaling
The Wnt (Wingless-related integration site) signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, etc [3].
The Wnt proteins are a diverse family of secreted lipid-modified signaling glycoproteins that are 350–400 amino acids in length. The type of lipid modification that occurs on these proteins is palmitoylation of cysteines in a conserved pattern of 23–24 cysteine residues. In Wnt signaling, these proteins act as ligands to activate the different Wnt pathways via paracrine and autocrine routes. These proteins are also highly conserved across species. They can be found in mice, humans, Xenopus, Zebrafish, Drosophila, and many others [3].
The tankyrases-a pair of enzymes that normally work by modifying a range of cellular proteins with ADP-ribose-are the best-validated downstream target for inhibiting WNT signaling [4.
References:
1. Voronkov, A.; et. al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem 2013, 56(7), 3012-3023.
2. Lau, T.; et. al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res 2013, 73(10), 3132-3144.
3. Cadigan, K. M.; et. al. Wnt signaling: a common theme in animal development. Genes Dev 1997, 11(24), 3286-3305.
4. Huang, S. M.; et. al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009, 461(7264), 614-620.
Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that ß-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/ß-catenin signaling and cell proliferation in intestinal crypts [2].
The biggest challenge to further development of G007-LK is its tolerability profile. In healthy mice, the compound blocked the regeneration of intestinal crypt cells, a normal process that depends on WNT signaling. Tankyrase inhibitors do not directly kill tumors but instead appear to block the self-renewal of undifferentiated cells with stem cell–like properties that are thought to be the source of colorectal tumors. Blocking tankyrases appears to drive those cells into a more differentiated state, thus reducing the supply of cancer stem cells.
Wnt Signaling
The Wnt (Wingless-related integration site) signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, etc [3].
The Wnt proteins are a diverse family of secreted lipid-modified signaling glycoproteins that are 350–400 amino acids in length. The type of lipid modification that occurs on these proteins is palmitoylation of cysteines in a conserved pattern of 23–24 cysteine residues. In Wnt signaling, these proteins act as ligands to activate the different Wnt pathways via paracrine and autocrine routes. These proteins are also highly conserved across species. They can be found in mice, humans, Xenopus, Zebrafish, Drosophila, and many others [3].
The tankyrases-a pair of enzymes that normally work by modifying a range of cellular proteins with ADP-ribose-are the best-validated downstream target for inhibiting WNT signaling [4.
References:
1. Voronkov, A.; et. al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem 2013, 56(7), 3012-3023.
2. Lau, T.; et. al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res 2013, 73(10), 3132-3144.
3. Cadigan, K. M.; et. al. Wnt signaling: a common theme in animal development. Genes Dev 1997, 11(24), 3286-3305.
4. Huang, S. M.; et. al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009, 461(7264), 614-620.
