Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition was written by Lang, Jessica D.;Hendricks, William P. D.;Orlando, Krystal A.;Yin, Hongwei;Kiefer, Jeffrey;Ramos, Pilar;Sharma, Ritin;Pirrotte, Patrick;Raupach, Elizabeth A.;Sereduk, Chris;Tang, Nanyun;Liang, Winnie S.;Washington, Megan;Facista, Salvatore J.;Zismann, Victoria L.;Cousins, Emily M.;Major, Michael B.;Wang, Yemin;Karnezis, Anthony N.;Sekulic, Aleksandar;Hass, Ralf;Vanderhyden, Barbara C.;Nair, Praveen;Weissman, Bernard E.;Huntsman, David G.;Trent, Jeffrey M.. And the article was included in Clinical Cancer Research in 2018.Category: pyrimidines The following contents are mentioned in the article:
Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Exptl. Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clin. approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclin. models through its inhibition of multiple kinases. Clin. investigation of this FDA-approved oncol. drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932-43. ©2018 AACR. This study involved multiple reactions and reactants, such as 1-(tert-Butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (cas: 219580-11-7Category: pyrimidines).
1-(tert-Butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (cas: 219580-11-7) belongs to pyrimidine derivatives. The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds and derivatives. Therapy for fungal infections is based mainly on four classes of antifungals: azoles, echinocandins, polyenes, and pyrimidine analogs.Category: pyrimidines
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Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia