生物活性

• 描述ACAT1 (Acyl-CoA Acyltransferase 1) is an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol. ATR-101, as an oral drug candidate in development for the treatment of Adrenocortical Cancer (ACC), is a selective and potent ACAT1 inhibitor with EC50 values of 9nM and 368nM for ACAT1 and ACAT2, respectively. Treatment with ATR-101 at concentration of 9nM for 5h decreased the formation of cholesteryl esters and increased free cholesterol levels in H295R human adrenocortical carcinoma cells in the presence of 45μg/ml cholesterol. Exogenous cholesterol could markedly potentiate the activity of ATR-101. ATR-101 led a dose-dependent inhibition of H295R cell growth at concentration ranging in 3nM-30μM post 24h and increased cell apoptosis at concentration of 30nM post 5-hour treatment, both in the presence of cholesterol. Dysregulation of ER calcium stores that resulted in ER stress and the UPR could also be observed after ATR-101 treatment. ATR-101 inhibited F1F0-ATP synthase and ATP synthesis in isolated mitochondria and elevated the mitochondrial membrane potential and depleted ATP concurrently in cells. It counteracted the establishment and growth of xenografts by ACC-derived H295R cells in SCID mice, but it did not shrink established xenografts.

• 动物研究
  剂量	Mice: 0.7 mg/kg[2] (p.o.) Dog: 3 mg/kg - 30 mg/kg[3] (p.o., BID)
  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
  NCT03669549	Congenital Adrenal Hyperplasia	Phase 2	Recruiting	March 2020	Czechia ... more >> Institute of Endocrinology Recruiting Praha 1, Czechia Contact: Katerina Lunakova    +420 224 905 357    endo@endo.cz    Principal Investigator: Jana Vrbikova, MD, PhD          France Hospital Cardiologique Louis Pradel, Groupement Hospitalier Est Not yet recruiting Bron, France Contact: Farida Smail       farida.smail@chu-lyon.fr    Principal Investigator: Aude Brac de la Perrière, MD          Hospital Pitié-Salpetrière Not yet recruiting Paris, France Contact: Jerome Dulon    +33 142 16 02 11    jerome.dulon@aphp.fr    Principal Investigator: Philippe Touraine, MD          Israel Bnai Zion Medical Center Not yet recruiting Haifa, Israel Contact: Michal Yeiches    +972-4-8359484    yeiches@gmail.com    Principal Investigator: Mohammad Sheikh-Ahmad, MD          Beilinson Hospital Not yet recruiting Petach Tikva, Israel Contact: Liat Rot    +972-39211403    liatro3@clalit.org.il    Principal Investigator: Ilan Shimon, MD          Tel-Aviv-Sourasky Medical Center Not yet recruiting Tel Aviv, Israel Contact: Miri Margaliot    +972-52-6110243    mirim@tlvmc.gov.il    Principal Investigator: Naftali Stern, MD          Spain Hospital General Universitario Gregorio Marañón Not yet recruiting Madrid, Spain Contact: Sara Calvo    +34 915 86 81 12    sara-calvo@hotmail.com    Principal Investigator: Rogelio Garcia Centeno, MD          Hospital Universitario Virgen del Rocío Not yet recruiting Sevilla, Spain Contact: Cristina Muñoz Gómez    +34 955 01 37 24    cmungom@hotmail.es    Principal Investigator: Miguel Ángel Mangas Cruz, MD          University Hospital La Fe Not yet recruiting Valencia, Spain Contact: Ana I Catalá    +34 961 24 55 54    catala_anagre@gva.es    Principal Investigator: Juan Francisco Merino-Torres, MD Collapse <<
  NCT03669549	Congenital Adrenal Hyperplasia	Phase 2	Recruiting	March 2020	Czechia ... more >> Institute of Endocrinology Recruiting Praha 1, Czechia Contact: Katerina Lunakova    +420 224 905 357    endo@endo.cz    Principal Investigator: Jana Vrbikova, MD, PhD          France Hospital Cardiologique Louis Pradel, Groupement Hospitalier Est Not yet recruiting Bron, France Contact: Farida Smail       farida.smail@chu-lyon.fr    Principal Investigator: Aude Brac de la Perrière, MD          Hospital Pitié-Salpetrière Not yet recruiting Paris, France Contact: Jerome Dulon    +33 142 16 02 11    jerome.dulon@aphp.fr    Principal Investigator: Philippe Touraine, MD          Israel Bnai Zion Medical Center Not yet recruiting Haifa, Israel Contact: Michal Yeiches    +972-4-8359484    yeiches@gmail.com    Principal Investigator: Mohammad Sheikh-Ahmad, MD          Beilinson Hospital Not yet recruiting Petach Tikva, Israel Contact: Liat Rot    +972-39211403    liatro3@clalit.org.il    Principal Investigator: Ilan Shimon, MD          Tel-Aviv-Sourasky Medical Center Not yet recruiting Tel Aviv, Israel Contact: Miri Margaliot    +972-52-6110243    mirim@tlvmc.gov.il    Principal Investigator: Naftali Stern, MD          Spain Hospital General Universitario Gregorio Marañón Not yet recruiting Madrid, Spain Contact: Sara Calvo    +34 915 86 81 12    sara-calvo@hotmail.com    Principal Investigator: Rogelio Garcia Centeno, MD          Hospital Universitario Virgen del Rocío Not yet recruiting Sevilla, Spain Contact: Cristina Muñoz Gómez    +34 955 01 37 24    cmungom@hotmail.es    Principal Investigator: Miguel Ángel Mangas Cruz, MD          University Hospital La Fe Not yet recruiting Valencia, Spain Contact: Ana I Catalá    +34 961 24 55 54    catala_anagre@gva.es    Principal Investigator: Juan Francisco Merino-Torres, MD Collapse <<

• 参考文献

• [1] LaPensee CR, Mann JE, et al. ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs. Endocrinology. 2016 May;157(5):1775-88.

  [2] Cheng Y, Kerppola RE, et al. ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo. Endocr Relat Cancer. 2016 Apr;23(4):1-19.