Tian, NN; Wu, HX; Zhang, HW; Yang, DN; Lv, L; Yang, ZC; Zhang, TT; Quan, DL; Zhou, L; Xie, Y; Xu, YM; Wei, N; Zhang, JJ; Chen, MA; Schmitz, JC; Tian, YX; Wu, SY in [Tian, Nannan; Wu, Huanxian; Zhang, Huiwu; Yang, Danni; Lv, Lin; Yang, Zichao; Zhang, Tingting; Quan, Dongling; Zhou, Lei; Zhang, Jiajie; Tian, Yuanxin; Shaoyu, Wu] Southern Med Univ, Guangdong Prov Key Lab New Drug Screening, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China; [Xie, Ying] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China; [Xu, Yimei] Ctr Dis Control & Prevent Xinjiang Uygur Autonomo, Urumqi 830002, Xinjiang, Peoples R China; [Wei, Ning; Schmitz, John C.] Univ Pittsburgh, Canc Therapeut Program, UPMC Hillman Canc Ctr, Pittsburgh, PA 15260 USA; [Chen, Mian] Oxford Univ Hosp NHS Fdn Trust, Oxford Transplant Ctr, Churchill Hosp, Old Rd, Oxford OX3 7LE, England; [Tian, Nannan] Guangzhou Univ Chinese Med, Key Lab Orthopaed & Traumatol, Affiliated Hosp 1, Clin Med Coll 1, Guangzhou, Peoples R China published Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo in 2020, Cited 35. Application In Synthesis of 2,4-Dichlorobenzoic acid. The Name is 2,4-Dichlorobenzoic acid. Through research, I have a further understanding and discovery of 50-84-0.
Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it’s necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Glil) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.
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Reference:
Chloride – Wikipedia,
,Chlorides – an overview | ScienceDirect Topics