生物活性

• 描述The smoothened (SMO) receptor is an essential component of the canonical Hedgehog (Hh) signaling pathway exerting a key role in the regulation of embryonic development, cell growth, and differentiation after embryogenesis in animals. LY2940680 (taladegib) is a potent Hh pathway inhibitor that binds to the human Smo receptor and competitively inhibits binding of an hSmo agonist. Oral administration of LY2940680 produced anti-tumor activity in the subcutaneous xenograft tumor stroma. Oral treatment of LY2940680 at 50 - 600 mg once daily resulted in an acceptable safety profile in patients with advanced cancer, including locally advanced and metastatic basal cell carcinoma. Oral LY2940680 at 100 - 400 mg once daily for 15 and 30 days resulted in a high level of inhibition of skin glioma-associated oncogene homolog 1 (Gli1) transcript levels in Japanese patients with advanced solid tumors.
• 作用机制The ligand LY2940680 binds in a pocket at the extracellular side of the SMO receptor formed by the seven transmembrane helical bundle and the extracellular domain linker domain and long extracellular loops.

• 动物研究
  剂量	Mice: 20 mg/kg[3] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02530437	Gastroesophageal Junction Aden... more >>ocarcinoma Stage IB Esophageal Adenocarcinoma AJCC v7 Stage II Esophageal Adenocarcinoma AJCC v7 Stage IIA Esophageal Adenocarcinoma AJCC v7 Stage IIB Esophageal Adenocarcinoma AJCC v7 Stage IIIA Esophageal Adenocarcinoma AJCC v7 Stage IIIB Esophageal Adenocarcinoma AJCC v7 Collapse <<	Phase 1 Phase 2	Active, not recruiting	March 31, 2023	United States, Texas ... more >> M D Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT02784795	Solid Tumor B... more >>reast Cancer Colon Cancer Cholangiocarcinoma Soft Tissue Sarcoma Collapse <<	Phase 1	Active, not recruiting	January 31, 2019	United States, Florida ... more >> Sylvester Comprehensive Cancer Center Miami, Florida, United States, 33136 United States, Michigan Karmanos Cancer Institute Detroit, Michigan, United States, 48201 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Denmark Rigshospitalet Copenhagen, København Ø, Denmark, 2100 France Institut Bergonie Bordeaux, France, 33076 Centre Leon Berard Lyon Cedex 08, France, 69373 Gustave Roussy Villejuif Cedex, France, 94805 Spain Hospital Universitari Vall d'Hebron Barcelona, Spain, 08035 Fundacion Jimenez Diaz Madrid, Spain, 28040 Hospital Madrid Norte Sanchinarro Madrid, Spain, 28050 Collapse <<
  NCT01681186	Healthy Volunteers	Phase 1	Completed	-	United States, Texas ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Dallas, Texas, United States Collapse <<

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• 参考文献

• [1] Redmond EM, Guha S, et al. Investigational Notch and Hedgehog inhibitors--therapies for cardiovascular disease. Expert Opin Investig Drugs. 2011 Dec;20(12):1649-64. doi: 10.1517/13543784.2011.628658. Epub 2011 Oct 18.

  [2] Hoch L, Faure H, et al. MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor. FASEB J. 2015 May;29(5):1817-29.