DeBio-1143 (AT-406)
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MedKoo CAT#: 204460

CAS#: 1071992-99-8 (free base)

Description: DeBio-1143, also known as AT-406, ARRY-334543and SM-406, is an orally bioavailable inhibitor of IAP (Inhibitor of Apoptosis Protein) family of proteins with potential apoptotic inducing and antineoplastic activity. AT-406 selectively inhibits the biological activity of IAP proteins, including X chromosome-linked IAP (XIAP), the cellular IAPs 1 (c-IAP1) and 2 (c-IAP2) and melanoma inhibitor of apoptosis protein (ML-IAP). This may restore and promote the induction of apoptosis through apoptotic signaling pathways. AT-406 may work synergistically with cytotoxic drugs to overcome tumor cell resistance to apoptosis.

Chemical Structure

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DeBio-1143 (AT-406)
CAS# 1071992-99-8 (free base)
Instruction

Theoretical Analysis

MedKoo Cat#: 204460
Name: DeBio-1143 (AT-406)
CAS#: 1071992-99-8 (free base)
Chemical Formula: C32H43N5O4
Exact Mass: 561.33
Molecular Weight: 561.730
Elemental Analysis: C, 68.42; H, 7.72; N, 12.47; O, 11.39

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1350 Ready to ship
500mg USD 2950 Ready to ship
1g USD 4950 Ready to ship
Bulk inquiry

Related CAS #: 1071992-99-8 (free base)   1071992-57-8 (HCl)   AT-406 mesylate    

Synonym: DeBio-1143; DeBio1143; DeBio 1143; AT-406; AT406; AT 406; SM 406; SM406; ARRY-334543; ARRY334543; ARRY 334543; Xevinapant

IUPAC/Chemical Name: (5S,8S,10aR)-N-benzhydryl-5-((S)-2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

InChi Key: LSXUTRRVVSPWDZ-MKKUMYSQSA-N

InChi Code: InChI=1S/C32H43N5O4/c1-21(2)19-28(38)36-18-17-25-15-16-27(37(25)32(41)26(20-36)34-30(39)22(3)33-4)31(40)35-29(23-11-7-5-8-12-23)24-13-9-6-10-14-24/h5-14,21-22,25-27,29,33H,15-20H2,1-4H3,(H,34,39)(H,35,40)/t22-,25+,26-,27-/m0/s1

SMILES Code: O=C([C@@H]1CC[C@@](CCN(C(CC(C)C)=O)C[C@@H]2NC([C@@H](NC)C)=O)([H])N1C2=O)NC(C3=CC=CC=C3)C4=CC=CC=C4

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

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: >2 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: IAPs are overexpressed by many cancer cell types, suppressing apoptosis by binding and inhibiting active caspases-3, -7 and -9 via their BIR (baculoviral lAP repeat) domains.

Biological target: Xevinapant (AT-406) is a potent and orally bioavailable Smac mimetic and an antagonist of IAPs, and it binds to XIAP, cIAP1, and cIAP2 proteins with Ki of 66.4, 1.9, and 5.1 nM, respectively.
In vitro activity: In order to determine the sensitivity of our panel of ovarian cancer cells to AT-406, a newly developed and orally active Smac mimetic that targets XIAP and cIAP1/2, these cells were treated with increasing doses of AT-406 for 48 h. These results revealed that 60% of the ovarian cancer cell lines tested were sensitive to AT-406 as a single agent as evident by their IC50 < 10μg/ml (Fig. 2A and B). To obtain more accurate IC50 values, additional cell viability assays were performed with additional lower doses of AT-406. These results indicated that the IC50 values of AT-406 in these ovarian cancer cells range from 0.05–0.5 µg/ml, indicating significant single agent activity in these cells (Fig. S1). To determine the type of cell death induced by AT-406, the panel of ovarian cancer cells were treated with increasing doses of AT-406 for 24 h and assessed the level of cleaved-PARP, a directly downstream substrate of caspase-3, which has been used routinely as an indicator of apoptosis. These results indicate that AT-406 promotes PARP cleavage in a dose-dependent manner (Fig. 2C), suggesting that AT-406 activates the apoptotic pathway. Reference: Cancer Biol Ther. 2012 Jul;13(9):804-11. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22669575/
In vivo activity: The plasma and tissue concentration–time profiles of observed data after 100 mg/kg dose of SM-406 were shown in Figure 3 (solid circles). The whole body PBPK model for SM-406 in MDA-MD-231 xenograft tumor bearing SCID mice is depicted in Figure 1. The physiological parameters for the whole body PBPK model were either obtained from the literature or determined by experiment and are listed in Table 1. The blood to plasma ratio (Kb/p) was 1.04 and the unbound fraction in plasma (fup) was 0.19. All equations were solved simultaneously with the maximum likelihood estimator in the ADAPT 5 software 22 and the fitted concentration–time profiles are shown in Figure 3 (solid lines). It appears from the graphs that the model captured the plasma concentration–time profiles quite well. After oral administration, the estimated first-order absorption rate constant was 0.974 h-1. Reference: Biopharm Drug Dispos. 2013 Sep;34(6):348-59. https://doi.org/10.1002/bdd.1850

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 25.0 44.50

Preparing Stock Solutions

The following data is based on the product molecular weight 561.73 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.

Recalculate based on batch purity %
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
Formulation protocol:
In vitro protocol: 1. Brunckhorst MK, Lerner D, Wang S, Yu Q. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012 Jul;13(9):804-11. doi: 10.4161/cbt.20563. Epub 2012 Jun 6. PMID: 22669575; PMCID: PMC3679100.
In vivo protocol: 1. Zhang T, Li Y, Zou P, Yu JY, McEachern D, Wang S, Sun D. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos. 2013 Sep;34(6):348-59. doi: 10.1002/bdd.1850. Epub 2013 Aug 2. PMID: 23813446.

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1: Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, Pfeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Theall KP, Lu DR, Bartlett CH, Koehler M, Fesl C, DeMichele A, Gnant M. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021 Feb;22(2):212-222. doi: 10.1016/S1470-2045(20)30642-2. Epub 2021 Jan 15. PMID: 33460574.


2: Vaduganathan M, Greene SJ, Zhang S, Grau-Sepulveda M, DeVore AD, Butler J, Heidenreich PA, Huang JC, Kittleson MM, Joynt Maddox KE, McDermott JJ, Owens AT, Peterson PN, Solomon SD, Vardeny O, Yancy CW, Fonarow GC. Applicability of US Food and Drug Administration Labeling for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in US Clinical Practice: The Get With the Guidelines-Heart Failure (GWTG-HF) Registry. JAMA Cardiol. 2020 Nov 13;6(3):1–10. doi: 10.1001/jamacardio.2020.5864. Epub ahead of print. PMID: 33185662; PMCID: PMC7666432.


3: Zhou R, Ma F, Su F, Ou Y, Qi Z, Zhang J, Huang Y, Dorenbos P, Liang H. Site Occupancies, VUV-UV-vis Photoluminescence, and X-ray Radioluminescence of Eu2+-Doped RbBaPO4. Inorg Chem. 2020 Dec 7;59(23):17421-17429. doi: 10.1021/acs.inorgchem.0c02714. Epub 2020 Nov 12. PMID: 33183001.


4: Li Z, Wang Q, Xia Y, Xun L, Liu H. A Red Fluorescent Protein-Based Probe for Detection of Intracellular Reactive Sulfane Sulfur. Antioxidants (Basel). 2020 Oct 13;9(10):985. doi: 10.3390/antiox9100985. PMID: 33066305; PMCID: PMC7602056.


5: Campbell GR, To RK, Zhang G, Spector SA. SMAC mimetics induce autophagy- dependent apoptosis of HIV-1-infected macrophages. Cell Death Dis. 2020 Jul 27;11(7):590. doi: 10.1038/s41419-020-02761-x. PMID: 32719312; PMCID: PMC7385130.


6: Chen H, Luo D, Shang B, Cao J, Wei J, Chen Q, Chen J. Immunoassay-type biosensor based on magnetic nanoparticle capture and the fluorescence signal formed by horseradish peroxidase catalysis for tumor-related exosome determination. Mikrochim Acta. 2020 Apr 21;187(5):282. doi: 10.1007/s00604-020-04275-x. PMID: 32318822.


7: Sarmah HJ, Mohanta D, Saha A. Perceptible exciton-to-trion conversion and signature of defect mediated vibronic modes and spin relaxation in nanoscale WS2 exposed to γ-rays. Nanotechnology. 2020 Apr 24;31(28):285706. doi: 10.1088/1361-6528/ab7c4a. Epub 2020 Mar 3. PMID: 32126535.


8: Bobardt M, Kuo J, Chatterji U, Wiedemann N, Vuagniaux G, Gallay P. The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice. PLoS One. 2020 Jan 24;15(1):e0227715. doi: 10.1371/journal.pone.0227715. PMID: 31978106; PMCID: PMC6980394.


9: Huang TX, Cong X, Wu SS, Lin KQ, Yao X, He YH, Wu JB, Bao YF, Huang SC, Wang X, Tan PH, Ren B. Probing the edge-related properties of atomically thin MoS2 at nanoscale. Nat Commun. 2019 Dec 5;10(1):5544. doi: 10.1038/s41467-019-13486-7. PMID: 31804496; PMCID: PMC6895227.


10: Zinngrebe J, Schlichtig F, Kraus JM, Meyer M, Boldrin E, Kestler HA, Meyer LH, Fischer-Posovszky P, Debatin KM. Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B-cell acute lymphoblastic leukemia. Int J Cancer. 2020 Jun 1;146(11):3219-3231. doi: 10.1002/ijc.32799. Epub 2019 Dec 10. PMID: 31749151.


11: Dong X, Zhao G, Li X, Miao J, Fang J, Wei Q, Cao W. Electrochemiluminescence immunoassay for the N-terminal pro-B-type natriuretic peptide based on resonance energy transfer between a self-enhanced luminophore composed of silver nanocubes on gold nanoparticles and a metal-organic framework of type MIL-125. Mikrochim Acta. 2019 Nov 19;186(12):811. doi: 10.1007/s00604-019-3969-5. PMID: 31745662.


12: Peilin W, Songsong T, Chengyu Z, Zhi C, Chunhui M, Yinxian Y, Lei Z, Min M, Zongyi W, Mengkai Y, Jing X, Tao Z, Zhuoying W, Fei Y, Chengqing Y. Directed elimination of senescent cells attenuates development of osteoarthritis by inhibition of c-IAP and XIAP. Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2618-2632. doi: 10.1016/j.bbadis.2019.05.017. Epub 2019 Jun 26. PMID: 31251987.


13: Gonçalves Dalkiranis G, Ferrando-Villalba P, Lopeandia-Fernández A, Abad- Muñoz L, Rodríguez-Viejo J. Thermoelectric Photosensor Based on Ultrathin Single-Crystalline Si Films †. Sensors (Basel). 2019 Mar 22;19(6):1427. doi: 10.3390/s19061427. PMID: 30909519; PMCID: PMC6471348.


14: Li X, Jiang X, Liu Q, Liang A, Jiang Z. Using N-doped Carbon Dots Prepared Rapidly by Microwave Digestion as Nanoprobes and Nanocatalysts for Fluorescence Determination of Ultratrace Isocarbophos with Label-Free Aptamers. Nanomaterials (Basel). 2019 Feb 7;9(2):223. doi: 10.3390/nano9020223. PMID: 30736465; PMCID: PMC6409902.


15: Bobardt M, Kuo J, Chatterji U, Chanda S, Little SJ, Wiedemann N, Vuagniaux G, Gallay PA. The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate. PLoS One. 2019 Feb 4;14(2):e0211746. doi: 10.1371/journal.pone.0211746. PMID: 30716099; PMCID: PMC6361451.


16: Thibault B, Genre L, Le Naour A, Broca C, Mery E, Vuagniaux G, Delord JP, Wiedemann N, Couderc B. DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death. Sci Rep. 2018 Dec 14;8(1):17862. doi: 10.1038/s41598-018-35860-z. PMID: 30552344; PMCID: PMC6294826.


17: Fu PY, Hu B, Ma XL, Yang ZF, Yu MC, Sun HX, Huang A, Zhang X, Wang J, Hu ZQ, Zhou CH, Tang WG, Ning R, Xu Y, Zhou J. New insight into BIRC3: A novel prognostic indicator and a potential therapeutic target for liver cancer. J Cell Biochem. 2019 Apr;120(4):6035-6045. doi: 10.1002/jcb.27890. Epub 2018 Oct 28. PMID: 30368883.


18: Tao Z, McCall NS, Wiedemann N, Vuagniaux G, Yuan Z, Lu B. SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer. Clin Cancer Res. 2019 Feb 1;25(3):1113-1124. doi: 10.1158/1078-0432.CCR-17-3852. Epub 2018 Oct 23. PMID: 30352911.


19: Tokuhara Y, Shukuya K, Tanaka M, Sogabe K, Ejima Y, Hosokawa S, Ohsaki H, Morinishi T, Hirakawa E, Yatomi Y, Shimosawa T. Absorbance measurements of oxidation of homogentisic acid accelerated by the addition of alkaline solution with sodium hypochlorite pentahydrate. Sci Rep. 2018 Jul 27;8(1):11364. doi: 10.1038/s41598-018-29769-w. PMID: 30054539; PMCID: PMC6063975.


20: Martínez Gámez MA, Vallejo H MA, Kiryanov AV, Licea-Jiménez L, Lucio M JL, Pérez-García SA. Fluorescence properties of Yb3+-Er3+ co- doped phosphate glasses containing silver nanoparticles. Methods Appl Fluoresc. 2018 Feb 15;6(2):024005. doi: 10.1088/2050-6120/aaab6c. PMID: 29447118.