Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A.

Autor: Leaver DJ, Cleary B, Nguyen N, Priebbenow DL, Lagiakos HR; Cancer Therapeutics CRC , 343 Royal Parade , Parkville , Victoria 3052 , Australia., Sanchez J; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Xue L; School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China., Huang F; School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China., Sun Y, Mujumdar P, Mudududdla R, Varghese S, Teguh S, Charman SA, White KL, Katneni K, Cuellar M; Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55455 , United States., Strasser JM; Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55455 , United States., Dahlin JL; Department of Pathology , Brigham and Women's Hospital, Boston , 75 Francis Street , Boston , Massachusetts 02115 , United States., Walters MA; Institute for Therapeutics Discovery and Development , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55455 , United States., Street IP; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Cancer Therapeutics CRC , 343 Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Monahan BJ; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Cancer Therapeutics CRC , 343 Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Jarman KE; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Sabroux HJ; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Falk H; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Cancer Therapeutics CRC , 343 Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Chung MC; ACRF Rational Drug Discovery Centre , St. Vincent's Institute of Medical Research , Fitzroy , Victoria 3065 , Australia., Hermans SJ; ACRF Rational Drug Discovery Centre , St. Vincent's Institute of Medical Research , Fitzroy , Victoria 3065 , Australia., Parker MW; ACRF Rational Drug Discovery Centre , St. Vincent's Institute of Medical Research , Fitzroy , Victoria 3065 , Australia., Thomas T; Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade , Parkville , Victoria 3052 , Australia.; Department of Medical Biology , University of Melbourne , Parkville , Victoria 3050 , Australia., Baell JB; School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China.; ARC Centre for Fragment-Based Design , Monash University , Parkville , Victoria 3052 , Australia.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Aug 08; Vol. 62 (15), pp. 7146-7159. Date of Electronic Publication: 2019 Jul 17.
DOI: 10.1021/acs.jmedchem.9b00665
Abstrakt: A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC 50 of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 ( 97 ), a highly potent inhibitor of KAT6A (IC 50 = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.
Databáze: MEDLINE