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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Approaches to telomerase inhibition have also been developed that do not directly inhibit the TERT or TR components of telomerase but instead inhibit proteins associated with telomerase activity. For example, the telomeric function of tankyrase I, a telomeric poly(ADP-ribose) polymerase (PARP) that can affect telomerase inhibition in cancer cells, has been targeted with small molecules. Signaling pathways such as those associated with mitogen-activated protein (MAP) kinase can result in stimulation of the TERT gene, and so these have also been targeted with small molecules in an attempt to reduce telomerase activity.
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
The cytoplasmic levels of APC, axin, and β-catenin offer additional approaches. Moreover, the activation state of cyclooxygenase (COX)-2 affects the intracellular level and stability of β-catenin. Increased COX-generated prostaglandin E2 suppresses β-catenin degradation, activating Wnt/β-catenin signaling. In that context, suppression of increased COX activity in cancer cells could explain aspirin’s anti-cancer effect. In addition, a small molecule has been identified that destabilizes β-catenin and RAS by binding to axin leading to suppression of stemness in CSCs [25]. Also, there are multiple small molecule drugs being investigated as tankyrase inhibitors. Tankyrase activates the Wnt pathway by degrading axin. It has been shown that inhibition of tankyrase downregulates c-KIT expression and inhibits growth in CD44-positive subpopulations of CRC-SCs [26].
Tankyrase inhibitors as antitumor agents: a patent update (2013 – 2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Chirag C. Mehta, Hardik G. Bhatt
The poly(ADP-ribose) polymerase (PARP) is a family of 17 known cellular enzyme proteins that majorly contribute toward maintaining cellular homeostasis. PARPs are also known as ADP-ribosyl transferases diphtheria toxin-like (ARTDs), poly(ADP-ribose)synthase (pARS) or poly(ADP-ribose)transferase (pARTs) [1]. Successful therapeutic application of FDA-approved PARP-1/2 inhibitor Olaparib drew the attention of researchers to investigate the potential of other enzymes of the PARP family as therapeutic targets [2]. After PARP-1/2; tankyrases are the most studied PARP enzymes due to their key role in many cellular activities and tumor-specific progression and proliferation [3]. PARP-1/2 is known to sense DNA damage followed by facilitating DNA repair and take part in many cellular activities such as necrosis, apoptosis, etc. Whereas tankyrases are involved with post-translational modification of different proteins which subsequently led to telomerase elongation, cellular division, Wnt-signaling inhibition, and cellular senescence [4].
Bone dynamics and inflammation: lessons from rare diseases
Published in Immunological Medicine, 2020
Yoshinori Matsumoto, Robert Rottapel
The research group of prof. Robert Rottapel’s lab (University of Toronto, Canada) uncovered the molecular mechanism underlying hyperosteoclastogenesis observed in cherubism patients. 3PB2 is tightly and negatively regulated by tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family (Figure 1(1)). Tankyrase-mediated 3BP2 ribosylation (Figure 1(2)) creates a recognition site for the E3-ubiquitin ligase RNF146 (Figure 1(3)), leading to ubiquitylation (Figure 1(4)) and proteasomal degradation (Figure 1(5)) of 3BP2 [9]. Gain-of-function cherubism mutations in the SH3BP2 gene uncouple 3BP2 from tankyrase and RNF146, stabilize the 3BP2 protein (Figure 2), and cause hyperactivation of SRC, SYK, and VAV. Osteoclasts derived from the cherubism mice showed increased endogenous 3BP2 protein levels and highly active SRC, SYK, and VAV [9], which in turn induce osteoclastogenesis. However, Sh3bp2–/– mice showed reduced bone resorption caused by defective cell-autonomous osteoclasts and impaired tyrosine kinase activation [13]. Constitutively active SRC rescues defective osteoclastogenesis observed in Sh3bp2–/– macrophages, demonstrating that 3BP2 is both sufficient and necessary for SRC kinase activation during osteoclastogenesis [13].