Discovery of 4-((3′ R ,4′ S ,5′ R )-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development
Open accessAbstract
We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure–activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
APG115 was shown to have very high affinity to MDM2 (Ki<1 nM) and potent cellular activity.
“Meanwhile, it was shown a very high affinity to MDM2 (Ki<1 nM), and potent cellular activity [26].”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [26]
Single-dose oral administration of APG-115 effectively activated p53 protein in SJSA-1 xenograft tumor in mice and caused complete and permanent regression of the tumor, as well as in RS4;11 AML model.
“Single-dose oral administration of APG-115 could effectively activate the p53 protein in SJSA-1 xenograft tumor in mice and cause complete and permanent regression of the tumor, as well as in RS4;11 AML model.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [46]
APG-115 showed a strong binding ability with MDM2 protein (Ki < 1 nM), activated p53 protein in a variety of tumor cells, inhibited cell proliferation at nM concentrations, and had enhanced selectivity over p53 knockout tumor cells.
“Compound 3 was used as the lead compound for a systematic structure–activity relationship study to obtain APG-115 (Fig. 10), which showed a strong binding ability with MDM2 protein (Ki < 1 nM) [46]. It could activate p53 protein in a variety of tumor cells and inhibit cell proliferation at nM concentrations, with an enhancement in its selectivity over p53 knockout tumor cells.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen
Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0897 · Cited by 6,763 · see citing works
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Applications of Fluorine in Medicinal Chemistry
Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J., & Meanwell, N. A. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00258 · Cited by 3,692 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Improved protein–ligand docking using GOLD
Verdonk, M. L., Cole, J. C., Hartshorn, M. J., Murray, C. W., & Taylor, R. D. (2003) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10465 · Cited by 3,073 · see citing works
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801 · see citing works
Eldridge, M., Murray, C. W., Auton, T. R., Paolini, G. V., & Mee, R. P. (1997) · Journal of Computer-Aided Molecular Design · doi:10.1023/a:1007996124545 · Cited by 1,692 · see citing works
Fluorine substituent effects (on bioactivity)
Smart, B. E. (2001) · Journal of Fluorine Chemistry · doi:10.1016/s0022-1139(01)00375-x · Cited by 1,502 · see citing works
p53 and Human Cancer: The First Ten Thousand Mutations
Hainaut, P. L., & Hollstein, M. C. (1999) · Advances in cancer research · doi:10.1016/s0065-230x(08)60785-x · Cited by 980 · see citing works
MDM2 — master regulator of the p53 tumor suppressor protein
Momand, J., Wu, H.-H., & Dasgupta, G. (2000) · Gene · doi:10.1016/s0378-1119(99)00487-4 · Cited by 641 · see citing works
Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development
Ding, Q., Zhang, Z., Liu, J.-J., Jiang, N., Zhang, J., Ross, T. M., Chu, X.-J., Bartkovitz, D., Podlaski, F., Janson, C., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400487c · Cited by 595 · see citing works
Functions of the MDM2 oncoprotein
Freedman, D. A., Wu, L., & Levine, A. J. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050273 · Cited by 573 · see citing works
Ray-Coquard, I., Blay, J.-Y., Italiano, A., Le Cesne, A., Penel, N., Zhi, J., Heil, F., Rueger, R., Graves, B., Ding, M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70474-6 · Cited by 571 · see citing works
Stepan, A. F., Subramanyam, C., Efremov, I. V., Dutra, J. K., O’Sullivan, T. J., DiRico, K. J., McDonald, W. S., Won, A. C., Dorff, P. H., Nolan, C. E., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300094u · Cited by 471 · see citing works
Zhao, Y., Aguilar, A., Bernard, D., & Wang, S. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501092z · Cited by 462 · see citing works
Self-citationSynthesis of Functionalized Oxazolines and Oxazoles with DAST and Deoxo-Fluor
Phillips, A. J., Uto, Y., Wipf, P., et al. (2000) · Organic Letters · doi:10.1021/ol005777b · Cited by 460 · see citing works
Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development
Vu, B., Wovkulich, P., Pizzolato, G., Lovey, A., Ding, Q., Jiang, N., Liu, J.-J., Zhao, C., Glenn, K., Wen, Y., et al. (2013) · ACS Medicinal Chemistry Letters · doi:10.1021/ml4000657 · Cited by 395 · see citing works
Targeting the MDM2-p53 Interaction for Cancer Therapy
Shangary, S. K., & Wang, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5136 · Cited by 364 · see citing works
Self-citationWang, S., Sun, W., Zhao, Y., McEachern, D., Meaux, I., Barrière, C., Stuckey, J. A., Meagher, J. L., Bai, L., Liu, L., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0799 · Cited by 328 · see citing works
Self-citationMDM2 is a Central Node in the p53 Pathway: 12 Years and Counting
Bond, G. L., Hu, W., & Levine, A. J. (2005) · Current Cancer Drug Targets · doi:10.2174/1568009053332627 · Cited by 310 · see citing works
Sun, D., Li, Z., Rew, Y., Gribble, M., Bartberger, M. D., Beck, H. P., Canon, J., Chen, A., Chen, X., Chow, D., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401753e · Cited by 290 · see citing works
Self-citationDiastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors
Zhao, Y., Liu, L., Sun, W., Lu, J., McEachern, D., Li, X., Yu, S., Bernard, D., Ochsenbein, P., Ferey, V., et al. (2013) · Journal of the American Chemical Society · doi:10.1021/ja3125417 · Cited by 234 · see citing works
Self-citationHolzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., Pissot-Soldermann, C., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00810 · Cited by 203 · see citing works
Juven‐Gershon, T., & Oren, M. (1999) · Molecular Medicine · doi:10.1007/bf03402141 · Cited by 193 · see citing works
p53 Activation by Small Molecules: Application in Oncology
Vassilev, L. T. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058174k · Cited by 172 · see citing works
Synthesis of 1,2,4-Oxadiazole-, 1,3,4-Oxadiazole-, and 1,2,4-Triazole-Derived Dipeptidomimetics
Borg, S., Estenne‐Bouhtou, G., Luthman, K., Csoeregh, I., Hesselink, W., & Hacksell, U. (1995) · The Journal of Organic Chemistry · doi:10.1021/jo00115a029 · Cited by 165 · see citing works
On the polarity of partially fluorinated methyl groups
Huchet, Q. A., Kuhn, B., Wagner, B., Fischer, H., Kansy, M., Zimmerli, D., Carreira, E. M., & Müller, K. (2013) · Journal of Fluorine Chemistry · doi:10.1016/j.jfluchem.2013.02.023 · Cited by 119 · see citing works
Zhang, Z., Chu, X., Liu, J., Ding, Q., Zhang, J., Bartkovitz, D., Jiang, N., Karnachi, P., So, S., Tovar, C., et al. (2013) · ACS Medicinal Chemistry Letters · doi:10.1021/ml400359z · Cited by 90 · see citing works
Aguilar, A., Sun, W., Liu, L., Lu, J., McEachern, D., Bernard, D., Deschamps, J. R., & Wang, S. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501541j · Cited by 79 · see citing works
Self-citationInhibitors of the p53/hdm2 protein–protein interaction—path to the clinic
Carry, J., & Garcı́a-Echeverrı́a, C. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.03.034 · Cited by 73 · see citing works
Targeting the MDM2-p53 protein–protein interaction for new cancer therapeutics
Wang, S., Zhao, Y., Bernard, D., Aguilar, A., & Kumar, S. (2012) · Topics in Medicinal Chemistry · doi:10.1007/978-3-642-28965-1_2 · Cited by 72 · see citing works
Self-citationTotal synthesis of (+)-nostocyclamide 1
Moody, C. J., & Bagley, M. C. (1998) · Journal of the Chemical Society Perkin Transactions 1 · doi:10.1039/a704094f · Cited by 67 · see citing works
Total Synthesis of (−)-Muscoride A
Wipf, P., & Venkatraman, S. (1996) · The Journal of Organic Chemistry · doi:10.1021/jo960891m · Cited by 66 · see citing works
Kerns, E. H., & Di, L. (2008) · Elsevier eBooks · doi:10.1016/b978-012369520-8.50015-2 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016 · see citing works
Self-citationLi, Y., Yang, J., Aguilar, A., McEachern, D., Przybranowski, S., Liu, L., Yang, C.-Y., Wang, M., Han, X., & Wang, S. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00909 · Cited by 312 · see citing works
Self-citationZhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., Jiang, Y., Yao, K., & Zhou, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01314-3 · Cited by 223 · see citing works
Fang, D. D., Tang, Q., Kong, Y., Wang, Q., Gu, J., Fang, X., Zou, P., Rong, T., Wang, J., Yang, D., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0750-6 · Cited by 151 · see citing works
Self-citationSmall molecules targeting protein–protein interactions for cancer therapy
Wu, D., Li, Y., Zheng, L., Xiao, H., Ouyang, L., Wang, G., & Sun, Q. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.05.035 · Cited by 71 · see citing works
Self-citationKocik, J., Machula, M., Wisniewska, A., Surmiak, E., Holak, T. A., & Skalniak, L. (2019) · Cancers · doi:10.3390/cancers11071014 · Cited by 46 · see citing works
Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides
Charoenpattarapreeda, J., Tan, Y. S., Iegre, J., Walsh, S. J., Fowler, E., Eapen, R. S., Wu, Y., Sore, H. F., Verma, C. S., Itzhaki, L., et al. (2019) · Chemical Communications · doi:10.1039/c9cc04022f · Cited by 35 · see citing works
Gicquel, M., Gomez, C., Garcia Alvarez, M. C., Pamlard, O., Guérineau, V., Jacquet, E., Bignon, J., Voituriez, A., & Marinetti, A. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01137 · Cited by 34 · see citing works
MDM2 inhibition in the treatment of glioblastoma: From concept to clinical investigation
Pellot Ortiz, K. I., Rechberger, J. S., Nonnenbroich, L. F., Daniels, D. J., & Sarkaria, J. N. (2023) · Biomedicines · doi:10.3390/biomedicines11071879 · Cited by 30 · see citing works
Chen, H., Luo, D., Zhang, L., Lin, X., Luo, Q., Yi, H., Wang, J., Yan, X., Li, B., Chen, Y., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17398 · Cited by 29 · see citing works
Self-citationGollner, A., Rudolph, D., Weyer-Czernilofsky, U., Baumgartinger, R., Jung, P., Weinstabl, H., Ramharter, J., Grempler, R., Quant, J., Rinnenthal, J., et al. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0783 · Cited by 18 · see citing works
- Authors
- Aguilar, A., Lu, J., Liu, L., Du, D., Bernard, D., McEachern, D., Przybranowski, S., Li, X., Luo, R., Wen, B., Sun, D., Wang, H., Wen, J., Wang, G., Zhai, Y., Guo, M., Yang, D., & Wang, S.
- Affiliations
- University of Michigan (US)
- University of Michigan , , 1600 Huron Parkway , , ,
- Jiangsu Ascentage Biomed Development Inc. , China Medical City, , ,
- Sun Yat-sen University Cancer Center (CN)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-03-24
- Volume
- 60
- Issue
- 7
- Pages
- 2819-2839
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC5394527
- OpenAlex
- W2600231982
- Cited by
- 211
- References
- 35
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 33 · 2023: 26 · 2022: 24 · 2021: 21 · 2020: 23 · 2019: 20 · 2018: 19 · 2017: 4
- FWCI
- 7.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA046592, R01CA121279)
- Ministry of Science and Technology of the People's Republic of China (2012AA020305, 2012ZX09401005)
- Guangdong Province (2013Y114)
- Ascentage Pharma Group Corporation, Ltd. (NA)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2 inhibitors, spirooxindoles, spirooxindole derivatives, structure-activity relationship, oral bioavailability, pharmacokinetics, tumor regression, cancer therapy
- MeSH terms
- Animals, Antineoplastic Agents, Bridged Bicyclo Compounds, Bone and Bones, Bone Neoplasms, Humans, Indoles, Leukemia, Neoplasms, Pyrrolidines, Osteosarcoma, Structure-Activity Relationship, Cell Line, Tumor, Mice, Rats, Proto-Oncogene Proteins c-mdm2, Halogenation, Drug Discovery, Molecular Docking Simulation
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 ›
Are you an author, or do you see a problem with this page? Request a review
