Small molecule SJ572946 activates BAK to initiate apoptosis
Giridhar Sekar,
Geetika Singh,
Xingping Qin,
Cristina D. Guibao,
Brittany Schwam,
Zintis Inde,
Christy R. Grace,
Weixing Zhang,
P. Jake Slavish,
Wenwei Lin,
Taosheng Chen,
Richard E. Lee,
Zoran Rankovic,
Kristopher Sarosiek,
Tudor Moldoveanu
Affiliations
Giridhar Sekar
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Geetika Singh
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Children’s GMP, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Xingping Qin
John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston,02115 MA, USA; Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, 02115 MA, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston,02115 MA, USA
Cristina D. Guibao
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Brittany Schwam
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Zintis Inde
John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston,02115 MA, USA; Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, 02115 MA, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston,02115 MA, USA
Christy R. Grace
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Weixing Zhang
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
P. Jake Slavish
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Wenwei Lin
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Taosheng Chen
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Richard E. Lee
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Zoran Rankovic
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Kristopher Sarosiek
John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston,02115 MA, USA; Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, 02115 MA, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston,02115 MA, USA
Tudor Moldoveanu
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Roeck, AR 72205, USA; Corresponding author
Summary: Poration of the outer mitochondrial membrane by the effector BCL-2 proteins BAK and BAX initiates apoptosis. BH3-only initiators BID and BIM trigger conformational changes in BAK and BAX transforming them from globular dormant proteins to oligomers of the apoptotic pores. Small molecules that can directly activate effectors are being sought for applications in cancer treatment. Here, we describe the small molecule SJ572946, discovered in a fragment-based screen that binds to the activation groove of BAK and selectively triggers BAK activation over that of BAX in liposome and mitochondrial permeabilization assays. SJ572946 independently kills BAK-expressing BCL2allKO HCT116 cells revealing on target cellular activity. In combination with apoptotic inducers and BH3 mimetics, SJ572946 kills experimental cancer cell lines. SJ572946 also cooperates with the endogenous BAK activator BID in activating a misfolded BAK mutant substantially impaired in activation. SJ572946 is a proof-of-concept tool for probing BAK-mediated apoptosis in preclinical cancer research.
