Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2.
Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a nontoxic and effective strategy for cancer therapy. However, a lack of specific Mnk inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of a novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II inhibitors. A selection of 66 compounds was tested for Mnk1 and Mnk2 inhibition, and 9 out of 20 active compounds showed type III interaction with an allosteric site of the proteins. Most of the type III inhibitors exhibited dual Mnk1 and Mnk2 activities and demonstrated potent antiproliferative properties against the MV4-11 acute myeloid leukemia cell line. Interestingly, ATP-/substrate-competitive inhibitors were found to be highly selective for Mnk2, with little or no activity for Mnk1. Our study suggests that Mnk1 and Mnk2 share a common structure of the allosteric inhibitory binding site but possess different structural features of the ATP catalytic domain. The findings will assist in the future design and development of Mnk targeted anticancer therapeutics.
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Sunita K C
SK
Basnet
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Sarah
S
Diab
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Raffaella
R
Schmid
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Mingfeng
M
Yu
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Yuchao
Y
Yang
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Todd Alexander
TA
Gillam
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Theodosia
T
Teo
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Peng
P
Li
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.).
Tom
T
Peat
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.) shudong.wang@unisa.edu.au Hugo.Albrecht@unisa.edu.au.
Hugo
H
Albrecht
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.) shudong.wang@unisa.edu.au Hugo.Albrecht@unisa.edu.au.
Shudong
S
Wang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000495:Allosteric Site; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007938:Leukemia / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D000255:Adenosine Triphosphate; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases