The ability of proteins to associate rests at the core of biology. Cellular architecture, information transfer, and chemical specificity rely upon highly precise recognition events; frequently these events involve the assembly of two or more proteins. The binding of two proteins may occur with low or high affinity, but clearly protein association in cells does not occur in a random, disorganized way. Rather, protein association is carefully scripted to achieve specific goals, be they the assembly of particular subcellular architectures or the relay of information (signal transduction). Proteinprotein association events may be recognized in all aspects of cell biochemistry. The mammalian immune response relies in large part upon the recognition of proteins and peptides by antibodies. Cell-cell recognition and attachment to the extracellular matrix is mediated by cell surface receptors (cadherins and integrins) that are ligated by protein partners such as actin and fibronection. Signal transduction from the cell surface to the nucleus is frequently mediated by one or more protein-protein associations, eg, Grb-2 binding to p185erbB2 to recruit its downstream target SOS to the membrane. Then, transcription itself is orchestrated by a plethora of transcription factors, activators, and suppressors, whose assembly is poorly understood but clearly important. Given the ubiquitous nature of these relationships, and the knowledge that inappropriate protein-protein binding can lead to disease, it should not be surprising that protein-protein interactions have attracted the attention of scientists in the pharmaceutical industry and elsewhere who are interested in producing inhibitors for use as biochemical tools or therapeutic agents. Indeed, there are ample examples in the literature of the use of antibodies, dominant negative proteins, or medium-sized peptides to inhibit particular protein-protein assemblies. In contrast, the discovery of small “drug-like” molecules that can perform a similar function has proven difficult. A number of special challenges are presented by targeting protein-protein binding in a drug discovery

† Abbreviations: AcpYEEK, N-acetyl-O-phospho-tyrosyl-glutamylglutamyl-lysine; Apaf-1, apoptotic protease activating factor-1; bcl-2, B-cell leukemia/lymphoma 2; bFGF, basic fibroblast growth factor; BH3, Bcl-2 homology domain 3; CHO, chinese hamster ovary; DHFR, dihydrofolate reductase; EGFr, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbent assay; ER, endoplasmic reticulum; FKBP, FK506-binding protein; FRET, fluorescence resonance energy transfer; GA, geldanamycin; Grb2, Growth factor receptor bound protein 2; GST, glutathione S-transferase; HIV, human immunodeficiency virus; GH, growth hormone; HRP, horseradish peroxidase; IL, interleukin; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; MW, molecular weight; NGF, nerve growth factor; NMR, nuclear magnetic resonance; NOx, nitric oxides; iNOS, inducible nitric oxide synthase; PARP, polyadenosylribose polymerase; PBMC, peripheral blood mononuclear cells; SAR, structure-activity relationship; SH2, src homology domain-2; PI, phosphatidyl-inositol; SOS, son-ofsevenless; TNF, tumor necrosis factor; zVADfmk, N-benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl ketone..* E-mail: Peter. toogood2@ pfizer. com. Tel:(734) 622 1335. Fax:(734) 622 1407.