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1.
Bioorg Med Chem Lett ; 15(3): 771-5, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15664855

ABSTRACT

Non-peptidic small molecule SMAC mimetics were designed and synthesized that bind to the BIR3 domain of XIAP using structure-based design. Substituted five-membered heterocycles such as thiazoles and imidazoles were identified that serve as replacements for peptide fragments of the lead.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Proteins/antagonists & inhibitors , Binding Sites , Drug Design , Heterocyclic Compounds/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Ligands , Magnetic Resonance Spectroscopy , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology , X-Linked Inhibitor of Apoptosis Protein
2.
J Med Chem ; 47(18): 4417-26, 2004 Aug 26.
Article in English | MEDLINE | ID: mdl-15317454

ABSTRACT

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.


Subject(s)
Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carrier Proteins/chemistry , Mitochondrial Proteins/chemistry , Peptide Fragments/therapeutic use , Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins , Binding Sites , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carrier Proteins/therapeutic use , Caspases/drug effects , Cell Division/drug effects , Cell Line, Tumor , Humans , Intracellular Signaling Peptides and Proteins , Ligands , Mice , Mitochondrial Proteins/therapeutic use , Peptide Fragments/chemistry , Protein Structure, Tertiary , Structure-Activity Relationship , Transplantation, Heterologous , X-Linked Inhibitor of Apoptosis Protein
3.
J Med Chem ; 47(7): 1709-18, 2004 Mar 25.
Article in English | MEDLINE | ID: mdl-15027862

ABSTRACT

Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been discovered using CrystaLEAD X-ray crystallographic high-throughput screening followed by structure-directed optimization. Screening of a 10 000 compound random library provided several low affinity leads and their corresponding X-ray crystal structures bound to the enzyme. The presence of a common structural feature in each of the leads suggested a strategy for the construction of a directed library of approximately 1000 compounds that were screened for inhibitory activity in a traditional enzyme assay. Several lead compounds with IC(50) values of about 1 microM against DHNA were identified, and crystal structures of their enzyme-bound complexes were obtained by cocrystallization. Structure-directed optimization of one of the leads thus identified afforded potent inhibitors with submicromolar IC(50) values.


Subject(s)
Aldehyde-Lyases/antagonists & inhibitors , Aldehyde-Lyases/chemistry , Benzoates/chemistry , Enzyme Inhibitors/chemistry , Neopterin/chemistry , Pyrimidines/chemistry , Triazoles/chemistry , Benzoates/chemical synthesis , Binding Sites , Crystallography, X-Ray , Databases, Factual , Enzyme Inhibitors/chemical synthesis , Guanine/analogs & derivatives , Guanine/chemical synthesis , Guanine/chemistry , Models, Molecular , Molecular Structure , Purines/chemistry , Pyrimidines/chemical synthesis , Structure-Activity Relationship , Triazoles/chemical synthesis
4.
J Med Chem ; 45(26): 5628-39, 2002 Dec 19.
Article in English | MEDLINE | ID: mdl-12477346

ABSTRACT

The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K(D) = 50 microM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.


Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Animals , Biological Availability , Catalytic Domain , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Magnetic Resonance Spectroscopy , Matrix Metalloproteinase 3/chemistry , Models, Molecular , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Naphthalenes/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Protein Binding , Rats , Structure-Activity Relationship
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