Tetrazole and acylsulfonamide bioisosteric replacements of the carboxylic acid in a dual MCL-1/BCL-xL inhibitor are tolerated

被引:4
作者
Chen, Lijia [1 ]
Lowe, Brandon [1 ]
Fletcher, Steven [1 ,2 ]
机构
[1] Univ Maryland, Sch Pharm, 20N Pine St, Baltimore, MD 21201 USA
[2] Univ Maryland, Greenebaum Canc Ctr, 20 S Greene St, Baltimore, MD 21201 USA
关键词
STRUCTURE-BASED DESIGN; MCL-1; INHIBITOR; DISCOVERY; PROTEINS;
D O I
10.1039/d3ra05711a
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Overexpression of the anti-apoptotic protein MCL-1 is associated with a plethora of human cancers, and it reduces the sensitivity of cancer cells to approved chemotherapies. Accordingly, the discovery of MCL-1 inhibitors is an active area of interest. Many inhibitors of the anti-apoptotic MCL-1 protein bear a crucial carboxylic acid that may engage Arg263 in the BH3-binding groove. We previously described the salicylic acid-based dual MCL-1/BCL-x(L) inhibitor 17cd, which is currently undergoing lead optimization. As part of that process, we wished to investigate bioisosteric replacement of 17cd's key carboxylic acid. Herein we describe the synthesis of a variety of analogues of a simpler analogue of 17cd presenting carboxylic acid surrogates. The acylsulfonamide and tetrazole motifs, which exhibit comparable pK(a)s to the carboxylic acid function, displayed similar, or better, binding affinities to MCL-1 and BCL-x(L) as the corresponding carboxylic acid-containing lead. Our best compound was acylsulfonamide 7d with a K-i of 800 nM against MCL-1 and 1.82 mM against BCL-x(L), and demonstrated an improved effect on the viability of the HL60 acute myeloid leukemia cell line relative to the parent carboxylic acid-containing dual inhibitor from which it was derived.
引用
收藏
页码:34322 / 34334
页数:13
相关论文
共 24 条
[1]   Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets [J].
Balko, Justin M. ;
Giltnane, Jennifer M. ;
Wang, Kai ;
Schwarz, Luis J. ;
Young, Christian D. ;
Cook, Rebecca S. ;
Owens, Phillip ;
Sanders, Melinda E. ;
Kuba, Maria G. ;
Sanchez, Violeta ;
Kurupi, Richard ;
Moore, Preston D. ;
Pinto, Joseph A. ;
Doimi, Franco D. ;
Gomez, Henry ;
Horiuchi, Dai ;
Goga, Andrei ;
Lehmann, Brian D. ;
Bauer, Joshua A. ;
Pietenpol, Jennifer A. ;
Ross, Jeffrey S. ;
Palmer, Gary A. ;
Yelensky, Roman ;
Cronin, Maureen ;
Miller, Vincent A. ;
Stephens, Phillip J. ;
Arteaga, Carlos L. .
CANCER DISCOVERY, 2014, 4 (02) :232-245
[2]   Carboxylic Acid (Bio)Isosteres in Drug Design [J].
Ballatore, Carlo ;
Huryn, Donna M. ;
Smith, Amos B., III .
CHEMMEDCHEM, 2013, 8 (03) :385-395
[3]   Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1) [J].
Chen, L. ;
Wilder, P. T. ;
Drennen, B. ;
Tran, J. ;
Roth, B. M. ;
Chesko, K. ;
Shapiro, P. ;
Fletcher, S. .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2016, 14 (24) :5505-5510
[4]   Discovery of N-sulfonylated aminosalicylic acids as dual MCL-1/BCL-xL inhibitors [J].
Chen, Lijia ;
Chauhan, Jay ;
Yap, Jeremy L. ;
Goodis, Christopher C. ;
Wilder, Paul T. ;
Fletcher, Steven .
RSC MEDICINAL CHEMISTRY, 2023, 14 (01) :103-112
[5]   A robust palladium-catalyzed cyanation procedure: beneficial effect of zinc acetate [J].
Chidambaram, R .
TETRAHEDRON LETTERS, 2004, 45 (07) :1441-1444
[6]   Mild, efficient and rapid O-debenzylation of ortho-substituted phenols with trifluoroacetic acid [J].
Fletcher, Steven ;
Gunning, Patrick T. .
TETRAHEDRON LETTERS, 2008, 49 (33) :4817-4819
[7]   MCL-1 inhibitors ? where are we now (2019)? [J].
Fletcher, Steven .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2019, 29 (11) :909-919
[8]   Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design [J].
Friberg, Anders ;
Vigil, Dominico ;
Zhao, Bin ;
Daniels, R. Nathan ;
Burke, Jason P. ;
Garcia-Barrantes, Pedro M. ;
Camper, DeMarco ;
Chauder, Brian A. ;
Lee, Taekyu ;
Olejniczak, Edward T. ;
Fesik, Stephen W. .
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (01) :15-30
[9]   Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia [J].
Glaser, Stefan P. ;
Lee, Erinna F. ;
Trounson, Evelyn ;
Bouillet, Philippe ;
Wei, Andrew ;
Fairlie, W. Douglas ;
Izon, David J. ;
Zuber, Johannes ;
Rappaport, Amy R. ;
Herold, Marco J. ;
Alexander, Warren S. ;
Lowe, Scott W. ;
Robb, Lorraine ;
Strasser, Andreas .
GENES & DEVELOPMENT, 2012, 26 (02) :120-125
[10]   BCL-2 family proteins: changing partners in the dance towards death [J].
Kale, Justin ;
Osterlund, Elizabeth J. ;
Andrews, David W. .
CELL DEATH AND DIFFERENTIATION, 2018, 25 (01) :65-80