Utilization of a β-Aminophosphotyrosyl Mimetic in the Design and Synthesis of Macrocyclic Grb2 SH2 Domain-Binding Peptides

Abstract

Grb2 SH2 domains are protein-docking modules that exert important functions in both normal and pathogenic signal transduction processes. Development of synthetic Grb2 SH2 domain binding ligands is being pursued by several groups as potential new therapies for a variety of diseases, including certain cancers. In these efforts, macrocyclization has been successfully utilized to take advantage of preferential recognition by Grb2 SH2 domains of ligands in beta-bend conformations. Recent examples of this approach include olefin-metathesis-derived macrocycles that employ ring closure at the beta-position of key pTyr-mimicking residues. In the current study, a novel phosphatase-stable beta-amino-pTyr mimetic designated "Pmp(beta)" was utilized to prepare variants of previously reported olefin-metathesis-derived macrocycles. An initial set of simplified cyclic peptides lacking key naphthyl side chain functionality was first synthesized to determine optimum ring size, with results indicating that a four-unit ring-closing segment was appropriate. On the basis of these findings, macrolactamization was undertaken with a more highly functionalized, naphthyl-containing gamma-amino acid analogue. The resulting cyclic beta-amino peptide is the first of a new class of pTyr-mimetic-containing ligands that may have utility in the development of antagonists of both Grb2 SH2 domains and other pTyr-dependent signaling systems.

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

“…193) was not repeated in their cADPcR counterparts. Derivatives 8-N 3 -cADPcR (200) and NH 2 -cADPcR (201) were full, albeit weak agonists of intracellular Ca 2+ -release in sea urchin homogenate and Human T-lymphocyte, indicating the importance of the "northern" ribosyl oxygen in determining activity. Similar modification was effected in the cyclic IDPribose series (e.g.…”

“…Alternative deployment of a (1-naphthyl)methanamido-allylglycine as pY+3 residue in this context has offered the potential for enhanced versatility of the procedure [199]. Macrolactamisation of an open-chain structure, presenting a (pY+0)--amino pTyr-mimetic (Pmp ), has also been investigated [200]. Compound 159 exhibited significantly higher binding affinity than openchain counterpart 150, due to decreased k d rate, and behaved in a manner consistent with a two-binding site model for interactions with Grb2-SH2 (K D = 97 pM and 72 nM respectively) [189].…”

The Synthesis of Macrocycles for Drug Discovery

“…Nonetheless, this chemical approach has been used to advantage to prepare both macrocyclic peptidomimetic and non-peptidic compounds, including renin inhibitors, [23][24][25][26][27] thrombin inhibitors (7, Figure 11.1, ring closure site and reagent used for cyclization indicated), 28,29 human immunodeficiency (HIV) protease inhibitors, 30,31 b-secretase (BACE-1) inhibitors, 32 TNF-a converting enzyme (TACE) inhibitors, 33 selective MMP-8 inhibitors, 34 protease inhibitors, 35 calpain inhibitors, 36 cholecystokinin (CCK)-B antagonists, 37 subtype selective somatostatin analogues, 38 growth factor receptor-bound protein 2 (Grb) Src homology 2 (SH2) domain inhibitors, 39 histone deacetylase (HDAC) inhibitors, 40 heat shock protein 90 (Hsp90) inhibitors, 41 PDZ domain ligands, 42 multicyclic mimics of protein loop structures, 43,44 and a wide variety of structures that target the G-quadruplex (8). [45][46][47] For this latter example, it was actually simultaneous double amide bond formation that created the ring.…”

Phosphate Isosteres in Medicinal Chemistry

“…Burke and co-workers [16][17][18][19][20][21][22][23] have utilised a Pmp group as a pTyr mimetic in a macrocyclic tetrapeptide inhibitor of the growth factor receptor-bound protein 2 (Grb2). Grb2 is an SH2 domain-containing docking module that participates in the oncogenic actions of certain PTKs, including erbB-2-dependent breast cancers and Met-dependent kidney cancers [18].…”

“…The simple phenyl DFKP (19) has an IC 50 value of 76 µM against PTP1B [43] whereas the corresponding phenyl DFMP shows an IC 50 value of 610 µM against the same target (Fig. (4)) [44].…”