Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152)
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A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.
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Researchers have developed related drugs, including GDC-0152, GDC-0917 (CUDC-427), LCL-161, AT-406 (Xevinapant, Debio1143), Birinapant (TL32711), ASTX-660.
“Researchers have developed related drugs, including GDC-0152 (184),459 GDC-0917 (CUDC-427) (185),460 LCL-161 (186),461 AT-406 (Xevinapant, Debio1143) (187),462 Birinapant (TL32711) (188),463 ASTX-660 (189).464”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [459]
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- Authors
- Flygare, J. A., Beresini, M., Budha, N., Chan, H., Chan, I. T., Cheeti, S., Cohen, F., Deshayes, K., Doerner, K., Eckhardt, S. G., Elliott, L. O., Feng, B., Franklin, M. C., Reisner, S. F., Gazzard, L., Halladay, J., Hymowitz, S. G., La, H., LoRusso, P., Maurer, B., Murray, L., Plise, E., Quan, C., Stephan, J.-P., Young, S. G., Tom, J., Tsui, V., Um, J., Varfolomeev, E., Vucic, D., Wagner, A. J., Wallweber, H. J. A., Wang, L., Ware, J., Wen, Z., Wong, H., Wong, J. M., Wong, M., Wong, S., Yu, R., Zobel, K., & Fairbrother, W. J.
- Affiliations
- Genentech (US)
- University of Colorado Anschutz (US)
- Wayne State University (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Flygare, John A.
- Fairbrother, Wayne J.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-03-28
- Volume
- 55
- Issue
- 9
- Pages
- 4101-4113
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC3366583
- OpenAlex
- W1998918148
- Cited by
- 252
- References
- 63
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 19 · 2023: 14 · 2022: 15 · 2021: 11 · 2020: 24 · 2019: 18 · 2018: 19 · 2017: 16 · 2016: 15 · 2015: 26 · 2014: 21 · 2013: 24 · 2012: 13
- FWCI
- 11.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Genentech
- National Center for Research Resources (P41RR001209)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- IAP antagonists, inhibitor of apoptosis proteins, XIAP, cIAP1, cIAP2, BIR3 domain, small molecule antagonists, caspase-3/7 activation, breast cancer, oral anticancer drugs, pharmacokinetics, plasma clearance, volume of distribution, MDA-MB-231 xenograft
- MeSH terms
- Baculoviral IAP Repeat-Containing 3 Protein, Animals, Antineoplastic Agents, Binding, Competitive, Breast Neoplasms, Cell Survival, Female, Humans, Male, Thiadiazoles, Apoptosis, Clinical Trials, Phase I as Topic, Caspases, Ubiquitin-Protein Ligases, Cell Line, Tumor, Inhibitor of Apoptosis Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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