Last update 01 Nov 2024

AXIN1 x TNKS2 x TNKS1

Last update 01 Nov 2024

Basic Info

Related Targets

AXIN1TNKS2TNKS1

Drugs associated with AXIN1 x TNKS2 x TNKS1

XAV-939

Target

AXIN1 x TNKS1 x TNKS2

Mechanism

AXIN1 stimulants [+2]

Active Org.-

Originator Org.

Cellzome AG [+1]

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with AXIN1 x TNKS2 x TNKS1

100 Translational Medicine associated with AXIN1 x TNKS2 x TNKS1

0 Patents (Medical) associated with AXIN1 x TNKS2 x TNKS1

Literatures (Medical) associated with AXIN1 x TNKS2 x TNKS1

07 Oct 2024·Journal of Cell Biology

A genome-wide screen links peroxisome regulation with Wnt signaling through RNF146 and TNKS/2

Article

Author: Gardner, Brooke M ; Richardson, Chris D ; Morrissey, Meghan A ; Sheedy, Connor J ; Mandjikian, Lori ; Chowdhury, Soham P ; Bacal, Julien ; Tavasoli, Katherine U ; Vu, Jonathan T

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced the import of proteins into peroxisomes. RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerases TNKS and TNKS2, which bind the peroxisomal membrane protein PEX14. We propose that RNF146 and TNKS/2 regulate peroxisome import efficiency by PARsylation of proteins at the peroxisome membrane. Interestingly, we found that the loss of peroxisomes increased TNKS/2 and RNF146-dependent degradation of non-peroxisomal substrates, including the β-catenin destruction complex component AXIN1, which was sufficient to alter the amplitude of β-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation but also a novel role in bridging peroxisome function with Wnt/β-catenin signaling during development.

01 Jan 2021·Iranian journal of pharmaceutical research : IJPRQ4 · MEDICINE

Tankyrase Inhibitor for Cardiac Tissue Regeneration: an In-silico Approach.

Q4 · MEDICINE

Article

Author: Amanlou, Massoud ; Amanlou, Arash ; Hosseini, Faezeh Sadat

Myocardial infarction causes heart tissue damages; therefore, using non-invasive methods to regenerate the heart tissue could be very helpful. Recent studies claimed that the inhibition of the Wnt signaling could promote cardiac remodeling and induce cardiac regeneration. Therefore, a tankyrase inhibitor to stabilize the AXIN and inhibit the Wnt/β-catenin signaling pathway will induce cardiac regeneration after injury. In this regard, virtual screening procedure, using molecular docking of 9127 FDA and world approved drugs, including herbal medicine, was done over the crystal structures of tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) catalytic poly (ADP-ribose) polymerase (PARP) domains with PDB ID: 2RF5 and 3KR7, respectively, to find potential small molecule inhibitors to regenerate injured heart tissue. Subsequently, molecular dynamics simulations were done to assess the stability of selected ligands phenothrin and ethyl rosinate in the binding pocket of TNKS1 and TNKS2 for 100 ns, respectively. Both compounds show suitable interaction in their binding pocket. The molecular dynamics simulation results confirm their stability. The binding free energy of complexes was carried out by the MM-PBSA method. ADME properties also indicate the potential of drug-likeness of both compounds. Taking together both drugs may be promising for inducing cardiac regeneration after injury. Nevertheless, clinical approval remains.

11 Apr 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors

Q1 · MEDICINE

Article

Author: Watanabe, Takashi ; Shirai, Fumiyuki ; Watanabe, Hirofumi ; Honma, Teruki ; Sato, Shin ; Shitara, Eiki ; Mazaki, Yui ; Shirouzu, Mikako ; Muramatsu, Yukiko ; Umehara, Takashi ; Yuki, Hitomi ; Okue, Masayuki ; Seimiya, Hiroyuki ; Koda, Yasuko ; Hirama, Chizuko ; Kano, Yuko ; Yoshimoto, Nobuko ; Kitamura, Kouichi ; Niwa, Hideaki ; Yoshida, Minoru ; Yoshida, Haruka ; Tsumura, Takeshi ; Washizuka, Kenichi ; Yashiroda, Yoko ; Mizutani, Anna ; Onuki, Tetsuo ; Chikada, Tsubasa ; Koyama, Hiroo ; Abe, Masako ; Fukami, Takehiro

The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as anticancer agents.

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