MedKoo product information:

Serdemetan

 JNJ-26854165 is an orally bioavailable, small-molecule HDM2 antagonist with potential antineoplastic activity. HDM2 antagonist JNJ-26854165 inhibits the binding of the HDM2–p53 complex to the proteasome, blocking the degradation of p53; p53 signaling and p53-mediated induction of tumor cell apoptosis may thus be restored. In addition to p53, degradation of other HDM2 client proteins may be inhibited. HDM2 (human homolog of double minute 2), a zinc finger protein, is a negative regulator of the p53 pathway; often overexpressed in cancer cells, this oncoprotein has been implicated in cancer cell proliferation and survival. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Serdemetan inhibited clonogenic survival in all cell lines, but in a lower extent in p53-null-HCT116. In the combination studies, Serdemetan treatment at 0.25μM in H460 and at 5μM in A549 cells resulted in a sensitivity-enhancement ratio of 1.18 and 1.36, respectively. At 2Gy, surviving fractions were 0.72 and 0.97 for p53-WT HCT116 and p53-null cells exposed to 0.5μM of Serdemetan, respectively (p<0.05). Radiosensitization of H460 and A549 cells was associated with G2/M cell cycle arrest and with an increased expression of p53 and p21. In vivo, Serdemetan caused a greater than additive increase in tumor growth delay. The dose enhancement factor was 1.9 and 1.6 for H460 and A549 tumors, respectively. Serdemetan inhibited proliferation, capillary tube formation and migration of HMEC-1 cells. These effects were more marked concurrently with irradiation. These results in tumor and endothelial cells suggest that Serdemetan has potential as a radiosensitizer. Further investigations are warranted with regard to the molecular mechanisms underlying its actions and its dependency regarding p53 status. (source: Cancer Lett. 2011 Dec 22;312(2):209-18. Epub 2011 Aug 22.).

Current developer:    Johnson and Johnson.

Serdemetan 881202-45-51: Chargari C, Leteur C, Angevin E, Bashir T, Schoentjes B, Arts J, Janicot M, Bourhis J, Deutsch E. Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts. Cancer Lett. 2011 Dec 22;312(2):209-18. Epub 2011 Aug 22. PubMed PMID: 21937165.

2: Smith MA, Gorlick R, Kolb EA, Lock R, Carol H, Maris JM, Keir ST, Morton CL, Reynolds CP, Kang MH, Arts J, Bashir T, Janicot M, Kurmasheva RT, Houghton PJ. Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2011 Sep 15. doi: 10.1002/pbc.23319. [Epub ahead of print] PubMed PMID: 21922647.

3: Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol. 2011 Apr 20;4:16. Review. PubMed PMID: 21504625; PubMed Central PMCID: PMC3103487.

4: Millard M, Pathania D, Grande F, Xu S, Neamati N. Small-molecule inhibitors of p53-MDM2 interaction: the 2006-2010 update. Curr Pharm Des. 2011;17(6):536-59. Review. PubMed PMID: 21391905.

5: Kojima K, Burks JK, Arts J, Andreeff M. The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. Mol Cancer Ther. 2010 Sep;9(9):2545-57. Epub 2010 Aug 24. PubMed PMID: 20736344; PubMed Central PMCID: PMC2949269.

6: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Apr;31(3):183-226. PubMed PMID: 19536362.