This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.
Idasanutlin, an MDM2 antagonist
Idasanutlin is an investigational small molecule designed to bind to murine double minute 2 (MDM2) and block its interaction with tumor protein 53 (TP53).1,2 By blocking MDM2-TP53 interaction, idasanutlin has the potential to upregulate TP53 and its tumor-suppressor functions. Preclinical studies in murine xenograft models have demonstrated that idasanutlin blocks the MDM2-TP53 interaction, resulting in tumor regression.1,2
1 Why target the MDM2-TP53 interaction in cancer?
The investigational small molecule idasanutlin is designed to target and bind to MDM2 to block its interaction with TP53.1,2 TP53 performs an array of tumor-suppressor functions, helping maintain genomic integrity of normal cells, and MDM2 serves as the primary negative regulator of TP53 activity. In certain cancers, aberrant expression of MDM2 can downregulate TP53 and its tumor-suppressor functions.3-7
2 How MDM2 inhibits TP53 tumor-suppressor functions
To carry out its tumor-suppressor functions, TP53 recognizes and binds to specific sequences in the DNA strand, triggering cellular processes that promote cell-cycle arrest, DNA repair, and apoptosis.3,4,8-11 MDM2 binds to TP53 to prevent it from binding to DNA and to facilitate its proteasomal degradation, thereby downregulating TP53 activity. Aberrant MDM2-TP53 interaction can limit the ability of TP53 to mount antitumor responses.5-7,12-15
3 Idasanutlin is designed to block MDM2 to induce antitumor responses
Idasanutlin is designed to bind to MDM2 and block its interaction with TP53.1,2 By blocking MDM2-TP53 interaction, idasanutlin has the potential to upregulate TP53 and its tumor-suppressor functions. Preclinical studies in murine xenograft models have demonstrated that idasanutlin blocks the MDM2-TP53 interaction, resulting in tumor regression.1,2 Genentech continues to investigate idasanutlin in ongoing clinical trials.16,17
- Lakoma A, Barbieri E, Agarwal S, et al. Cell Death Discov. 2015;1. pii: 15026. doi:10.1038/cddiscovery.2015.26. PMID: 26998348
- Lehmann C, Friess T, Birzele F, Kiialainen A, Dangl M. J Hematol Oncol. 2016;9:50. doi:10.1186/s13045-016-0280-3. PMID: 27353420
- Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. Nature. 1993;362:847-849. PMID: 8479522
- Hwang BJ, Ford JM, Hanawalt PC, Chu G. Proc Natl Acad Sci U S A. 1999;96:424-428. PMID: 9892649
- Bond GL, Hu W, Bond EE, et al. Cell. 2004;119:591-602. PMID: 15550242
- Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Nature. 1993;362:857-860. PMID: 8479525
- Shi D, Gu W. Genes Cancer. 2012;3:240-248. PMID: 23150757
- Zauberman A, Barak Y, Ragimov N, Levy N, Oren M. EMBO J. 1993;12:2799-2808. PMID: 8334996
- el-Deiry WS, Harper JW, O'Connor PM, et al. Cancer Res. 1994;54:1169-1174. PMID: 8118801
- Van Nguyen T, Puebla-Osorio N, Pang H, Dujka ME, Zhu C. J Exp Med. 2007;204:1453-1461. PMID: 17535972
- Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM. Nat Med. 2005;11:1306-1313. PMID: 16286925
- Momand J, Zambetti GP, Olson DC, George D, Levine AJ. Cell. 1992;69:1237-1245. PMID: 1535557
- Kussie PH, Gorina S, Marechal V, et al. Science. 1996;274:948-953. PMID: 8875929
- Kubbutat MH, Jones SN, Vousden KH. Nature. 1997;387: 299-303. PMID: 9153396
- Honda R, Tanaka H, Yasuda H. FEBS Lett. 1997;420:25-27. PMID: 9450543
- US National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02545283. Accessed February 15, 2019.
- US National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02670044. Accessed February 15, 2019.