Publications (11)82.39 Total impact
-
Article: Structure-guided design of a selective BCL-XL inhibitor.
[show abstract] [hide abstract]
ABSTRACT: The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-XL will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-XL-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-XL from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-XL for their sustained growth.Nature Chemical Biology 04/2013; · 14.69 Impact Factor -
Article: Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
[show abstract] [hide abstract]
ABSTRACT: ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.Journal of Medicinal Chemistry 03/2011; 54(6):1914-26. · 4.80 Impact Factor -
Article: Small-molecule pan-IAP antagonists: a patent review.
[show abstract] [hide abstract]
ABSTRACT: The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival that have become important targets for therapeutic intervention in human malignancies. One strategy for targeting IAP proteins involves agents that mimic the amino terminus of the endogenous IAP protein antagonist second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low pI (DIABLO) and thus block critical IAP protein interactions. This review of the IAP antagonist patent literature covers the period from 2000 to mid-2009. Over 50 patents and patent applications pertaining to IAP antagonists have been published over the past 10 years. In the case of several filings, only the original source is reviewed in this analysis. Readers will gain an overview of IAP protein antagonist scaffolds, with representative examples including monovalent and bivalent Smac mimetics, and an understanding of their structure-activity relationships. The feasibility of disrupting IAP protein interactions with pro-apoptotic proteins using monovalent and bivalent Smac-derived peptidomimetic compounds has been broadly established. Four such compounds have entered or been approved to enter human clinical trials, which will hopefully allow the utility of this potential therapeutic approach to be evaluated in cancer patients.Expert Opinion on Therapeutic Patents 02/2010; 20(2):251-67. · 3.57 Impact Factor -
Article: Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres.
[show abstract] [hide abstract]
ABSTRACT: A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compounds, 19a and 33b, were found to have K(i)'s of 20-30 nM against ML-IAP and 50-60 nM against XIAP-BIR3.Bioorganic & medicinal chemistry letters 02/2010; 20(7):2229-33. · 2.65 Impact Factor -
Article: Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.
[show abstract] [hide abstract]
ABSTRACT: The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their functional characterization as activators of apoptosis in tumor cells. Although capable of inducing cell death and preventing clonogenic survival, c-IAP-selective antagonists are significantly less potent in promoting apoptosis when compared to pan-selective compounds. However, both pan-IAP- and c-IAP-selective antagonists stimulate c-IAP1 and c-IAP2 degradation and activation of NF-kappaB pathways with comparable potencies. Therefore, although compounds that specifically target c-IAP1 and c-IAP2 are capable of inducing apoptosis, antagonism of the c-IAP proteins and XIAP is required for efficient induction of cancer cell death by IAP antagonists.ACS Chemical Biology 06/2009; 4(7):557-66. · 6.45 Impact Factor -
Article: Development of novel drugs targeting inhibitors of apoptosis.
Future Oncology 04/2009; 5(2):141-4. · 3.16 Impact Factor -
Article: Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold.
[show abstract] [hide abstract]
ABSTRACT: A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.Journal of Medicinal Chemistry 03/2009; 52(6):1723-30. · 4.80 Impact Factor -
Article: IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
[show abstract] [hide abstract]
ABSTRACT: Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.Cell 12/2007; 131(4):669-81. · 32.40 Impact Factor -
Article: Correction: Design, Synthesis, and Biological Activity of a Potent Smac Mimetic That Sensitizes Cancer Cells to Apoptosis by Antagonizing IAPs
10/2006; -
Article: Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs.
[show abstract] [hide abstract]
ABSTRACT: Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rationale is based on a combination of phage-panning data, peptide binding studies, and a survey of potential isosteres. The synthesis of two scaffolds is described. These compounds bind the XIAP-baculoviral IAP repeat 3 (BIR3), cIAP1-BIR3, cIAP2-BIR3, and ML-IAP-BIR domains with submicromolar affinities. The most potent Smac mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a K i of 50 nM. The X-ray crystal structure of this compound bound to an ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with a phage-derived tetrapeptide, AVPW. The structures show that these compounds bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns and similar hydrophobic interactions. Consistent with the structural data, coimmunoprecipitation experiments demonstrate that the compounds can effectively block Smac interactions with ML-IAP. The compounds are further demonstrated to activate caspase-3 and -7, to reduce cell viability in assays using MDA-MB-231 breast cancer cells and A2058 melanoma cells, and to enhance doxorubicin-induced apoptosis in MDA-MB-231 cells.ACS Chemical Biology 10/2006; 1(8):525-33. · 6.45 Impact Factor -
Article: Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP).
[show abstract] [hide abstract]
ABSTRACT: Melanoma inhibitor of apoptosis (ML-IAP) is a potent anti-apoptotic protein that is upregulated in a number of melanoma cell lines but not expressed in most normal adult tissues. Overexpression of IAP proteins, such as ML-IAP or the ubiquitously expressed X-chromosome-linked IAP (XIAP), in human cancers has been shown to suppress apoptosis induced by a variety of stimuli. Peptides based on the processed N-terminus of Smac/DIABLO can negate the ability of overexpressed ML-IAP or XIAP to suppress drug-induced apoptosis. Such peptides have been demonstrated to bind to the single baculovirus IAP repeat (BIR) of ML-IAP and the third BIR of XIAP with similar high affinities (approximately 0.5 microM). Herein, we use phage-display of naïve peptide libraries and synthetic peptides to investigate the peptide-binding properties of ML-IAP-BIR and XIAP-BIR3. X-ray crystal structures of ML-IAP-BIR in complex with Smac- and phage-derived peptides, together with peptide structure-activity-relationship data, indicate that the peptides can be modified to provide increased binding affinity and selectivity for ML-IAP-BIR relative to XIAP-BIR3. For instance, substitution of Pro3' in the Smac-based peptide (AVPIAQKSE) with (2S,3S)-3-methylpyrrolidine-2-carboxylic acid [(3S)-methyl-proline] results in a peptide with 7-fold greater affinity for ML-IAP-BIR and about 100-fold specificity for ML-IAP-BIR relative to XIAP-BIR3.Biochemistry 08/2003; 42(27):8223-31. · 3.42 Impact Factor
Top co-authors
Top Journals
Institutions
-
2009–2010
-
Genentech
- Department of Discovery Chemistry
San Francisco, CA, USA
-
