33757-53-8Relevant academic research and scientific papers
Highly potent and isoform selective dual site binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have antiproliferative activity
Nathubhai, Amit,Haikarainen, Teemu,Koivunen, Jarkko,Murthy, Sudarshan,Koumanov, Fran?oise,Lloyd, Matthew D.,Holman, Geoffrey D.,Pihlajaniemi, Taina,Tosh, David,Lehti?, Lari,Threadgill, Michael D.
, p. 814 - 820 (2017)
Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939)5, i.e., IC50 = 100 pM vs TNKS2 and IC50 = 6.5 μM vs PARP1 for 14. In cellular assays, 13 and 14 inhibited Wnt-signaling, enhanced insulin-stimulated glucose uptake, and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 1.
Rational design, synthesis and biological evaluation of dual PARP-1/2 and TNKS1/2 inhibitors for cancer therapy
Xu, Yizhu,Wu, Huanhuan,Huang, Lei,Zhai, Bingxin,Li, Xiaofei,Xu, Shuaiqi,Wu, Xingxin,Zhu, Qihua,Xu, Qiang
, (2022/05/04)
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are the first and most successful drugs designed to exploit the concept of synthetic lethality (SL) between PARP-1 and BRCA1/2, which provides a novel strategy for tumor treatment. However, narrowed indications and resistance to PARP-1 inhibitors have hampered their further clinical application. Inducing “BRCAness” by targeting other targets, which will directly or indirectly disturb the homologous recombination (HR) repair pathway of double-strand DNA breaks (DSBs), is a promising strategy for expanding the clinical application of PARP-1 inhibitors and overcoming resistance to these inhibitors. Tankyrase1/2 (TNKS1/2) are involved in the nonhomologous end-joining (NHEJ) DNA repair pathway by regulating Wnt/β-catenin signaling. TNKS1/2 can also induce a “BRCAness” phenotype by regulating Wnt signaling, which increases the sensitivity of tumor cells with BRCA proficiency to PARP-1 inhibitors. These results suggest that cotargeting PARP1/2 and TNKS1/2 not only exerts a synergistic effect in the treatment of tumors but also provides a novel strategy for expanding the clinical application of PARP-1 inhibitors and overcoming resistance to PARP-1 inhibitors. Therefore, a series of dual PARP-1/2 and TNKS1/2 inhibitors were rationally designed, synthesized, and evaluated for their pharmacological properties. Among these candidates, compound I-9 showed excellent inhibitory activity as it inhibited PARP-1/2 and TNKS1/2 with IC50 values of 0.25 nM, 1.2 nM, 13.5 nM and 4.15 nM, respectively. I-9 exhibited favorable synergistic antitumor efficacy in both BRCA-mutant and BRCA-wild-type cancer lines. Moreover, I-9 exerted prominent dose-dependent antitumor activity in an HCT116 cell-derived xenograft model and was significantly more efficacious than olaparib and E7449. Overall, the present study indicated that I-9, a dual PARP-1/2 and TNKS1/2 inhibitor, is a novel and promising agent for cancer therapy.
1, 8-naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline as well as synthesis and application thereof
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, (2021/02/20)
The invention discloses naphthalene anhydride derivatives containing 8-(benzoylamino) quinoline as well as a preparation method and application thereof, and belongs to the field of biological organicsynthesis. According to the naphthalic anhydride derivat
TANKYRASE INHIBITORS
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, (2018/03/28)
The invention relates to compounds of formula (I): (I) and salts, solvates, tautomers and stereoisomers thereof, where the definitions of the variables are provided herein. The invention also relates to pharmaceutical compositions comprising compounds of formula (I) as well as for the use of such compounds as tankyrase inhibitors and for the treatment of diseases such as cancer.
WNT INHIBITORS FOR HUMAN STEM CELL DIFFERENTIATION
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Paragraph 0176; 0177, (2013/07/19)
Methods and small molecule compounds for stem cell differentiation and treatment of animals with diseases are provided. One example of a class of compounds that may be used is represented by the compound of Formula I and II: or a pharmaceutically acceptab
Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: A structure-activity relationship study based on inhibitors for the Wnt response
Lanier, Marion,Schade, Dennis,Willems, Erik,Tsuda, Masanao,Spiering, Sean,Kalisiak, Jaroslaw,Mercola, Mark,Cashman, John R.
, p. 697 - 708 (2012/04/10)
Human embryonic stem cell-based high-content screening of 550 known signal transduction modulators showed that one "lead" (1, a recently described inhibitor of the proteolytic degradation of Axin) stimulated cardiomyogenesis. Because Axin controls canonical Wnt signaling, we conducted an investigation to determine whether the cardiogenic activity of 1 is Wnt-dependent, and we developed a structure-activity relationship to optimize the cardiogenic properties of 1. We prepared analogues with a range of potencies (low nanomolar to inactive) for Wnt/β-catenin inhibition and for cardiogenic induction. Both functional activities correlated positively (r 2 = 0.72). The optimal compounds induced cardiogenesis 1.5-fold greater than 1 at 30-fold lower concentrations. In contrast, no correlation was observed for cardiogenesis and modulation of transforming growth factor β (TGFβ)/Smad signaling that prominently influences cardiogenesis. Taken together, these data show that Wnt signaling inhibition is essential for cardiogenic activity and that the pathway can be targeted for the design of druglike cardiogenic molecules.
