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Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II.

ABSTRACT: Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure-activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC₅₀ inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.

SUBMITTER: Leenders RGG

PROVIDER: S-EPMC8713164 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.

Project description:Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.

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Dichloridotetra-kis-(1H-1,2,4-triazole-?N(4))copper(II).

Project description:The central Cu(II) atom of the molecular title complex, [CuCl(2)(C(2)H(3)N(3))(4)], is situated on a site with symmetry 2.22. It is six-coordinated in an elongated octa-hedral geometry, with the equatorial plane defined by four N atoms of four 1,2,4-triazole ligands and the axial positions occupied by two Cl atoms situated on a twofold axis. The mol-ecules are connected via N-H?Cl hydrogen bonds and the crystal consists of two inter-penetrating three-dimensional hydrogen-bonded frameworks.

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Diaqua-bis(1H-1,2,4-triazole-3-carboxyl-ato)cadmium(II).

Project description:In the title complex, [Cd(C(3)H(2)N(3)O(2))(2)(H(2)O)(2)], the Cd(II) atom is coordinated by two N and two O atoms from two deprotonated 1H-1,2,4-triazole-3-carboxylic acid ligands (TRIA) and two water mol-ecules. The Cd atom is located on an inversion centre. In the crystal structure, mol-ecules are linked together via O-H?O and N-H?O hydrogen bonds, forming a three-dimensional network.

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Bis[triaqua-(1H-1,2,4-triazole-3,5-dicarboxyl-ato-?O,N)copper(II)] di-?-aqua-bis-[diaqua-(1H-1,2,4-triazole-3,5-dicarboxyl-ato-?O,N)copper(II)].

Project description:In the title compound, [Cu(C(4)HN(3)O(4))(H(2)O)(3)](2)[Cu(2)(C(4)HN(3)O(4))(2)(H(2)O)(6)], both monomeric and dimeric mol-ecules are present in the solid state. In the monomeric compound, the Cu(II) atom is five-coordinated in a square-pyramidal configuration by one O atom and one N atom from one 1H-1,2,4-triazole-3,5-dicarboxyl-ate (TZDCA(2-)) ligand and three O atoms from water mol-ecules. In the centrosymmetric binuclear complex, each Cu(II) atom is six-coordinated in an octa-hedral geometry by one O atom and one N atom from one TZDCA(2-) ligand and four O atoms from water mol-ecules, two of which bridge the Cu(II) atoms. In the structure, there are intra-molecular O-H?O and N-H?O hydrogen bonds, and in the crystal, inter-molecular O-H?O, O-H?N and N-H?O hydrogen bonds link symmetry-related mol-ecules, forming a three-dimensional supra-molecular structure.

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Nitrato(1,10-phenanthroline)(1H-1,2,4-triazole-3-carboxyl-ato)copper(II).

Project description:In the title complex, [Cu(C(3)H(2)N(3)O(2))(NO(3))(C(12)H(8)N(2))], the Cu(II) ion is coordinated by an N and an O atom from a bidentate 1H-1,2,4-triazole-3-carboxyl-ate (TRIA) ligand, two N atoms from a 1,10-phenanthroline (phen) ligand, and an O atom from a nitrate ligand in a slightly distorted square-pyramidal environment. In the crystal structure, inter-molecular N-H?O hydrogen bonds link mol-ecules into one-dimensional chains propagating along the b axis direction.

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Bis(?-4-amino-3,5-dimethyl-4H-1,2,4-triazole)bis-[diiodidozinc(II)].

Project description:In the title compound, [Zn(2)I(4)(C(4)H(8)N(4))(2)], the Zn(II) atom is coordinated in a distorted tetra-hedral geometry by two N atoms from the triazole rings of two 4-amino-3,5-dimethyl-4H-1,2,4-triazole (admt) ligands and two iodide ligands. Doubly bridging admt ligands connect two Zn(II) atoms, forming a centrosymmetric dimer. Weak N-H?I and C-H?I hydrogen bonds play an important role in the inter-molecular packing.

| S-EPMC3050150 | biostudies-literature

Poly[dichloridobis[?-1-(4-pyridylmeth-yl)-1H-1,2,4-triazole]copper(II)].

Project description:The title coordination polymer, [CuCl(2)(C(8)H(8)N(4))(2)](n), arose from a layer-separated diffusion synthesis at room temperature. The Cu atom (site symmetry ) is coordinated by two chloride ions and four N atoms (two from triazole rings and two from pyridyl rings) in a distorted trans-CuCl(2)N(4) octa-hedral arrangement. The bridging 1-(4-pyridylmeth-yl)-1H-1,2,4-triazole ligands [dihedral angle between the triazole and pyridine rings = 68.08?(8)°] result in a two-dimensional 4(4) sheet structure in the crystal.

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catena-Poly[[dibromidozinc(II)]-?-4-(3-pyrid-yl)-4H-1,2,4-triazole].

Project description:The title complex, [ZnBr(2)(C(7)H(6)N(4))](n), was formed under hydro-thermal conditions using the ligand 4-(3-pyrid-yl)-4H-1,2,4-triazole (L). The unique Zn(II) ion is coordinated by one triazole N atom, one pyridine N atom and two Br atoms in a slightly distorted tetra-hedral coordination environment. Symmetry-related Zn(II) ions are connected by bridging L ligands into chains parallel to [001] in which the Zn?Zn separation is 8.643?(7)?Å. In the crystal structure, weak inter-molecular C-H?Br hydrogen bonds link the chains into a three-dimensional network.

| S-EPMC3007524 | biostudies-literature

Chlorido(1,10-phenanthroline)(1H-1,2,4-triazole-3-carboxyl-ato)copper(II).

Project description:The title complex, [Cu(C(3)H(2)N(3)O(2))Cl(C(12)H(8)N(2))], crystallizes with two independent mol-ecules in the asymmetric unit. Each Cu(II) atom is coordinated by an N atom and an O atom from the bidentate 1H-1,2,4-triazole-3-carboxyl-ate ligand, two N atoms from the 1,10-phenanthroline ligand, and the Cl atom. The coordination geometry is based on a ClN(3)O square pyramid. In the crystal structure, the mol-ecules are linked by inter-molecular N-H⋯O hydrogen bonds.

| S-EPMC2914951 | biostudies-literature

A new copper(II) complex based on 1-[(1H-benzotriazol-1-yl)meth-yl]-1H-1,2,4-triazole.

Project description:The title complex, tetra-aqua-{1-[(1H-benzotriazol-1-yl)meth-yl]-1H-1,2,4-triazole-κN(4)}(sulfato-κO)copper(II) sesquihydrate, [Cu(SO(4))(C(9)H(8)N(6))(H(2)O)(4)]·1.5H(2)O, is composed of one copper atom, one 1-[(2H-benzotriazol-1-yl)meth-yl]-1-H-1,2,4-triazole (bmt) ligand, one sulfate ligand, four coordin-ated water mol-ecules and one and a half uncoordinated water mol-ecules. The Cu(II) atom is six-coordinated by one N atom from a bmt ligand and five O atoms from the monodentate sulfate ligand and four water mol-ecules in a distorted octa-hedral geometry. In the crystal, adjacent mol-ecules are linked through O-H⋯O and O-H⋯N hydrogen bonds involving the sulfate anion and the coordin-ated and uncoordinated water mol-ecules into a three-dimensional network.

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