Synthesis and utilization of chiral alpha-methylated alpha-amino acids with a carboxyalkyl side chain in the design of novel Grb2-SH2 peptide inhibitors free of phosphotyrosine.
The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. To improve the potency and bioavailability of the Grb2-SH2 inhibitors, the chiral alpha-methyl-alpha-carboxyalkyl amino acid [(alpha-Me)Aa] was designed to cover dual structural and functional features separately contributed by 1-aminocyclohexanecarboxylic acid (Ac6c) and alpha-aminoadipic acid (Adi) in position Y + 1. The enantiopure l(or D)-(alpha-Me)Aa bearing various chain length carboxylalkyl side chain was conveniently synthesized by an optimized oxazolidinone methodology. The incorporation of (S)-(alpha-Me)Aa into the non-pTyr-containing peptide framework with a 5-amino acid sequence binding motif of X (-2)-Leu-(3'-substituted-Tyr) (0)-X (+1)-Asn really improved the inhibitory activity, affording potent (R)-sulfoxide-bridged cyclic and an open-chain series of pentapeptide inhibitors of Grb2-SH2 domain (IC 50 = 1.1-5.8 microM). More significantly, these (alpha-Me)Aa incorporated peptide inhibitors showed excellent activities in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with low micromolar IC 50 values, owing to the reduced peptidic nature and absence of pTyr or pTyr mimetics.
Long
Ya-Qiu
YQ
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. yqlong@mail.shcnc.ac.cn
Xue
Ting
T
Song
Yan-Li
YL
Liu
Zu-Long
ZL
Huang
Shao-Xu
SX
Yu
Qiang
Q
D000478:Alkylation; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015195:Drug Design; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009369:Neoplasms / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D000596:Amino Acids; D002264:Carboxylic Acids; D051380:GRB2 Adaptor Protein; D010455:Peptides