Examination of phosphoryl-mimicking functionalities within a macrocyclic Grb2 SH2 domain-binding platform.
Reported herein are the design, synthesis, and Grb2 SH2 domain-binding affinities of several phosphoryl-mimicking groups displayed within the context of a conformationally constrained macrocyclic platform. With use of surface plasmon resonance techniques, single-digit nanomolar affinities were exhibited by phosphonic acid and malonyl-containing diacidic phosphoryl mimetics (for 4h and 4g, K(D) = 1.47 and 3.62 nM, respectively). Analogues containing monoacidic phosphoryl mimetics provided affinities of K(D) = 16-67 nM. Neutral phosphoryl-mimicking groups did not show appreciable binding.
Kang
Sang-Uk
SU
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Shi
Zhen-Dan
ZD
Worthy
Karen M
KM
Bindu
Lakshman K
LK
Dharmawardana
Pathirage G
PG
Choyke
Sarah J
SJ
Bottaro
Donald P
DP
Fisher
Robert J
RJ
Burke
Terrence R
TR
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D004797:Enzyme-Linked Immunosorbent Assay; D051380:GRB2 Adaptor Protein; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018716:Molecular Mimicry; D010755:Organophosphates / Q000737:chemistry*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D047028:Macrocyclic Compounds; D010755:Organophosphates