title: Examination of phosphoryl-mimicking functionalities within a macrocyclic Grb2 SH2 domain-binding platform.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Kang
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Lakshman K
authors.initials: LK
authors.lastname: Bindu
authors.forename: Pathirage G
authors.initials: PG
authors.lastname: Dharmawardana
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Choyke
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: 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
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D047028:Macrocyclic Compounds; D010755:Organophosphates