WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H205509
CAS#: 1005342-46-0
Description: LCL161 is a n orally bioavailable second mitochondrial-derived activator of caspases (SMAC) mimetic and inhibitor of IAP (Inhibitor of Apoptosis Protein) family of proteins, with potential antineoplastic activity. SMAC mimetic LCL161 binds to IAPs, such as X chromosome-linked IAP (XIAP) and cellular IAPs 1 and 2. Since IAPs shield cancer cells from the apoptosis process, this agent may restore and promote the induction of apoptosis through apoptotic signaling pathways in cancer cells. IAPs are overexpressed by many cancer cell types and suppress apoptosis by binding and inhibiting active caspases-3, -7 and -9, which play essential roles in apoptosis (programmed cell death), necrosis and inflammation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).
Hodoodo Cat#: H205509
Name: LCL-161
CAS#: 1005342-46-0
Chemical Formula: C26H33FN4O3S
Exact Mass: 500.23
Molecular Weight: 500.630
Elemental Analysis: C, 62.38; H, 6.64; F, 3.79; N, 11.19; O, 9.59; S, 6.40
Synonym: LCL161; LCL 161; LCL-161
IUPAC/Chemical Name: (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide
InChi Key: UFPFGVNKHCLJJO-SSKFGXFMSA-N
InChi Code: InChI=1S/C26H33FN4O3S/c1-16(28-2)24(33)30-22(17-7-4-3-5-8-17)26(34)31-14-6-9-21(31)25-29-20(15-35-25)23(32)18-10-12-19(27)13-11-18/h10-13,15-17,21-22,28H,3-9,14H2,1-2H3,(H,30,33)/t16-,21-,22-/m0/s1
SMILES Code: C[C@H](NC)C(N[C@@H](C1CCCCC1)C(N2[C@H](C3=NC(C(C4=CC=C(F)C=C4)=O)=CS3)CCC2)=O)=O
Appearance: Solid powder
Purity: >98%
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: LCL161, a SMAC mimetic, was tested against the PPTP in vitro panel (1.0 nM to 10.0 µM) and the PPTP in vivo panels (30 or 75 mg/kg [solid tumors] or 100 mg/kg [ALL]) administered orally twice in a week. LCL161 showed a median relative IC(50) value of >10 µM, being more potent against several leukemia and lymphoma lines. In vivo LCL161 induced significant differences in EFS distribution in approximately one-third of solid tumor xenografts (osteosarcoma and glioblastoma), but not in ALL xenografts. No objective tumor responses were observed. In vivo LCL161 demonstrated limited single agent activity against the pediatric preclinical models studied. (source: Pediatr Blood Cancer. 2011 Jun 16. doi: 10.1002/pbc.23167. [Epub ahead of print]).
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The following data is based on the product molecular weight 500.63 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
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| In vivo protocol: |
1: Shekhar TM, Green MM, Rayner DM, Miles MA, Cutts SM, Hawkins CJ. Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells. Mutat Res. 2015 Jul;777:23-32. doi: 10.1016/j.mrfmmm.2015.04.005. Epub 2015 Apr 15. PubMed PMID: 25916945.
2: Fulda S. Targeting inhibitor of apoptosis proteins for cancer therapy: a double-edge sword? J Clin Oncol. 2014 Oct 1;32(28):3190-1. doi: 10.1200/JCO.2014.56.8741. Epub 2014 Aug 11. PubMed PMID: 25113757.
3: Infante JR, Dees EC, Olszanski AJ, Dhuria SV, Sen S, Cameron S, Cohen RB. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014 Oct 1;32(28):3103-10. doi: 10.1200/JCO.2013.52.3993. Epub 2014 Aug 11. PubMed PMID: 25113756.
4: Tian A, Wilson GS, Lie S, Wu G, Hu Z, Hebbard L, Duan W, George J, Qiao L. Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells. Cancer Lett. 2014 Sep 1;351(2):232-41. doi: 10.1016/j.canlet.2014.06.006. Epub 2014 Jun 27. PubMed PMID: 24976294.
5: Faye MD, Beug ST, Graber TE, Earl N, Xiang X, Wild B, Langlois S, Michaud J, Cowan KN, Korneluk RG, Holcik M. IGF2BP1 controls cell death and drug resistance in rhabdomyosarcomas by regulating translation of cIAP1. Oncogene. 2015 Mar 19;34(12):1532-41. doi: 10.1038/onc.2014.90. Epub 2014 Apr 7. PubMed PMID: 24704827.
6: Ramakrishnan V, Painuly U, Kimlinger T, Haug J, Rajkumar SV, Kumar S. Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma. Leukemia. 2014 Jul;28(7):1519-28. doi: 10.1038/leu.2014.2. Epub 2014 Jan 9. PubMed PMID: 24402161; PubMed Central PMCID: PMC4090267.
7: Vázquez-Sánchez EA, Rodríguez-Romero M, Sánchez-Torres LE, Rodríguez-Martínez S, Cancino-Diaz JC, Rodríguez-Cortes O, García-López ES, Cancino-Diaz ME. Peptidoglycan from Staphylococcus aureus has an anti-apoptotic effect in HaCaT keratinocytes mediated by the production of the cellular inhibitor of apoptosis protein-2. Microbiol Immunol. 2014 Feb;58(2):87-95. doi: 10.1111/1348-0421.12126. PubMed PMID: 24372854.
8: Fulda S. Molecular pathways: targeting inhibitor of apoptosis proteins in cancer--from molecular mechanism to therapeutic application. Clin Cancer Res. 2014 Jan 15;20(2):289-95. doi: 10.1158/1078-0432.CCR-13-0227. Epub 2013 Nov 22. Review. PubMed PMID: 24270683.
9: Qin Q, Zuo Y, Yang X, Lu J, Zhan L, Xu L, Zhang C, Zhu H, Liu J, Liu Z, Tao G, Dai S, Zhang X, Ma J, Cai J, Sun X. Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. Tumour Biol. 2014 Mar;35(3):2565-74. doi: 10.1007/s13277-013-1338-2. Epub 2013 Oct 30. PubMed PMID: 24170321.
10: Sauer M, Reiners KS, Hansen HP, Engert A, Gasser S, von Strandmann EP. Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro. Biol Chem. 2013 Oct;394(10):1325-31. doi: 10.1515/hsz-2013-0161. PubMed PMID: 23787466.
11: Dhuria S, Einolf H, Mangold J, Sen S, Gu H, Wang L, Cameron S. Time-dependent inhibition and induction of human cytochrome P4503A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects. J Clin Pharmacol. 2013 Jun;53(6):642-53. doi: 10.1002/jcph.79. Epub 2013 Apr 15. PubMed PMID: 23585187.
12: Yuan Z, Syrkin G, Adem A, Geha R, Pastoriza J, Vrikshajanani C, Smith T, Quinn TJ, Alemu G, Cho H, Barrett CJ, Arap W, Pasqualini R, Libutti SK. Blockade of inhibitors of apoptosis (IAPs) in combination with tumor-targeted delivery of tumor necrosis factor-α leads to synergistic antitumor activity. Cancer Gene Ther. 2013 Jan;20(1):46-56. doi: 10.1038/cgt.2012.83. Epub 2012 Nov 16. PubMed PMID: 23154431; PubMed Central PMCID: PMC3534156.
13: Knights AJ, Fucikova J, Pasam A, Koernig S, Cebon J. Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. Cancer Immunol Immunother. 2013 Feb;62(2):321-35. doi: 10.1007/s00262-012-1342-1. Epub 2012 Aug 26. PubMed PMID: 22923192.
14: Chen KF, Lin JP, Shiau CW, Tai WT, Liu CY, Yu HC, Chen PJ, Cheng AL. Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem Pharmacol. 2012 Aug 1;84(3):268-77. doi: 10.1016/j.bcp.2012.04.023. Epub 2012 May 9. PubMed PMID: 22580047.
15: Houghton PJ, Kang MH, Reynolds CP, Morton CL, Kolb EA, Gorlick R, Keir ST, Carol H, Lock R, Maris JM, Billups CA, Smith MA. Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2012 Apr;58(4):636-9. doi: 10.1002/pbc.23167. Epub 2011 Jun 16. PubMed PMID: 21681929; PubMed Central PMCID: PMC3253328.
16: Weisberg E, Ray A, Barrett R, Nelson E, Christie AL, Porter D, Straub C, Zawel L, Daley JF, Lazo-Kallanian S, Stone R, Galinsky I, Frank D, Kung AL, Griffin JD. Smac mimetics: implications for enhancement of targeted therapies in leukemia. Leukemia. 2010 Dec;24(12):2100-9. doi: 10.1038/leu.2010.212. Epub 2010 Sep 16. Erratum in: Leukemia. 2011 Jul;25(7):1221. PubMed PMID: 20844561; PubMed Central PMCID: PMC4037865.
