Idasanutlin

(RG7388)

Breast
  • Phase
  • I
  • II
  • III
Gastrointestinal
  • Phase
  • I
  • II
  • III
Genitourinary
  • Phase
  • I
  • II
  • III
Gynecologic
  • Phase
  • I
  • II
  • III
Hematology
  • Phase
  • I
  • II
  • III
Lung
  • Phase
  • I
  • II
  • III
Melanoma
  • Phase
  • I
  • II
  • III
Solid Tumor
  • Phase
  • I
  • II
  • III

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

Idasanutlin image: An investigational MDM2 antagonist currently being studied for its potential to block the interaction of MDM2  with TP53

 

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

Idasanutlin image: Idasanutlin is designed to block MDM2 to induce antitumor responses

 

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

Idasanutlin image: By blocking MDM2-TP53 interaction, idasanutlin has the potential to upregulate TP53 and its tumor-suppressor functions

References

  1. Lakoma A, Barbieri E, Agarwal S, et al. Cell Death Discov. 2015;1. pii: 15026. doi:10.1038/cddiscovery.2015.26. PMID: 26998348
  2. 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
  3. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. Nature. 1993;362:847-849. PMID: 8479522
  4. Hwang BJ, Ford JM, Hanawalt PC, Chu G. Proc Natl Acad Sci U S A. 1999;96:424-428. PMID: 9892649
  5. Bond GL, Hu W, Bond EE, et al. Cell. 2004;119:591-602. PMID: 15550242
  6. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Nature. 1993;362:857-860. PMID: 8479525
  7. Shi D, Gu W. Genes Cancer. 2012;3:240-248. PMID: 23150757
  8. Zauberman A, Barak Y, Ragimov N, Levy N, Oren M. EMBO J. 1993;12:2799-2808. PMID: 8334996
  9. el-Deiry WS, Harper JW, O'Connor PM, et al. Cancer Res. 1994;54:1169-1174. PMID: 8118801
  10. Van Nguyen T, Puebla-Osorio N, Pang H, Dujka ME, Zhu C. 
J Exp Med. 2007;204:1453-1461. PMID: 17535972
  11. Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM. Nat Med. 2005;11:1306-1313. PMID: 16286925
  12. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. Cell. 1992;69:1237-1245. PMID: 1535557
  13. Kussie PH, Gorina S, Marechal V, et al. Science. 1996;274:948-953. PMID: 8875929
  14. Kubbutat MH, Jones SN, Vousden KH. Nature. 1997;387:
299-303.
PMID: 9153396
  15. Honda R, Tanaka H, Yasuda H. FEBS Lett. 1997;420:25-27. PMID: 9450543
  16. US National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02545283. Accessed February 15, 2019.
  17. US National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02670044. Accessed February 15, 2019.

Related links

Explore MDM2

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Information Based on Tumor Type

Read About Clinical Trials

Idasanutlin proposed MOA

Watch this video for an in-depth look at the proposed mechanism of action for idasanutlin.