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APG-1387 (SM-1387) is a novel and potent IAP inhibitoris with anticancer effects, acting by promoting the rapid degradation of cIAP1/2 and XIAP, enhancing the chemosensitivity and promoting apoptosis in combination with CDDP and 5-FU of NPC in vitro and vivo.
Physicochemical Properties
| Molecular Formula | C60H72N10O10S2 |
| Molecular Weight | 1157.4047 |
| Exact Mass | 1156.487 |
| CAS # | 1570231-89-8 |
| PubChem CID | 73336238 |
| Appearance | White to off-white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Index of Refraction | 1.681 |
| LogP | 4.09 |
| Hydrogen Bond Donor Count | 6 |
| Hydrogen Bond Acceptor Count | 14 |
| Rotatable Bond Count | 18 |
| Heavy Atom Count | 82 |
| Complexity | 2240 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | S(C1C([H])=C([H])C([H])=C(C=1[H])S(N1C([H])([H])[C@@]([H])(C(N2[C@]([H])(C(N([H])C([H])(C3C([H])=C([H])C([H])=C([H])C=3[H])C3C([H])=C([H])C([H])=C([H])C=3[H])=O)C([H])([H])C([H])([H])[C@]2([H])C([H])([H])C1([H])[H])=O)N([H])C([C@]([H])(C([H])([H])[H])N([H])C([H])([H])[H])=O)(=O)=O)(N1C([H])([H])[C@@]([H])(C(N2[C@]([H])(C(N([H])C([H])(C3C([H])=C([H])C([H])=C([H])C=3[H])C3C([H])=C([H])C([H])=C([H])C=3[H])=O)C([H])([H])C([H])([H])[C@]2([H])C([H])([H])C1([H])[H])=O)N([H])C([C@]([H])(C([H])([H])[H])N([H])C([H])([H])[H])=O)(=O)=O |
| InChi Key | AKLBERUGKZNEJY-RTEPGWBGSA-N |
| InChi Code | InChI=1S/C60H72N10O10S2/c1-39(61-3)55(71)63-49-37-67(34-32-45-28-30-51(69(45)59(49)75)57(73)65-53(41-18-9-5-10-19-41)42-20-11-6-12-21-42)81(77,78)47-26-17-27-48(36-47)82(79,80)68-35-33-46-29-31-52(70(46)60(76)50(38-68)64-56(72)40(2)62-4)58(74)66-54(43-22-13-7-14-23-43)44-24-15-8-16-25-44/h5-27,36,39-40,45-46,49-54,61-62H,28-35,37-38H2,1-4H3,(H,63,71)(H,64,72)(H,65,73)(H,66,74)/t39-,40-,45+,46+,49-,50-,51-,52-/m0/s1 |
| Chemical Name | (5S,8S,10aR)-3-[3-[[(5S,8S,10aR)-8-(benzhydrylcarbamoyl)-5-[[(2S)-2-(methylamino)propanoyl]amino]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-3-yl]sulfonyl]phenyl]sulfonyl-N-benzhydryl-5-[[(2S)-2-(methylamino)propanoyl]amino]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | In HepG2 and HCCLM3 cells, dasminapant (0.02–20 μM; 24 hours) causes fast cIAP degradation [1]. In HepG2 and HCCLM3 cells, dasminapant (2 μM; 24 hours) increases TNF-α and TRAIL-mediated anticancer activity. HepG2 and HCCLM3 cells are made more susceptible to NK cell-mediated death in vitro by dasminapant [1]. |
| ln Vivo | Dasminapant (20 mg/kg; intraperitoneally every 3 days for 4 weeks) sensitizes HCCLM3 tumors to NK cell-mediated killing in mice [1]. Dasminapant (20 mg/kg; intraperitoneally every 3 days for 4 weeks) monotherapy showed modest antitumor effects and was well tolerated in mice [1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: HepG2 and HCCLM3 Cell Tested Concentrations: 0.02, 0.2, 2, 20 μM Incubation Duration: 1, 6, 24 hrs (hours) Experimental Results: At a certain dose and dosage, the expression of cIAP1 and cIAP2 in both cell lines Expressions are all diminished in a time-dependent manner. Inhibits the expression of X chromosome-linked IAP (XIAP) at high doses. |
| Animal Protocol |
Animal/Disease Models: Non-obese diabetic and severe combined immunodeficiency (NOD-SCID) mice bearing HCCLM3 tumors were injected with NK cells [1] Doses: 20 mg/kg Route of Administration: intraperitoneally (ip) (ip) every 3 days for 4 weeks Experimental Results: cIAP1 expression was diminished and cIAP2 had a weak effect on XIAP expression. Enhanced effects of preactivated NK cells on HCCLM3 xenograft tumor growth and tumor weight. |
| References |
[1]. The SMAC Mimetic APG-1387 Sensitizes Immune-Mediated Cell Apoptosis in Hepatocellular Carcinoma. Front Pharmacol. 2018 Nov 6; 9:1298. [2]. Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway. J Exp Clin Cancer Res. 2018 Mar 12;37(1):53. [3]. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis. Cancer Lett. 2016 Oct 10;381(1):14-22. [4]. Abstract 6216: Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer. American Association for Cancer Research. Aug 2020. 80(16). [5]. Abstract 1754: Smac mimetics APG-1387 synergizes with immune checkpoint inhibitors in preclinical models. American Association for Cancer Research. Jul 2018. 78(13). |
| Additional Infomation |
APG-1387 is under investigation in clinical trial NCT04568265 (A Clinical Study of APG-1387 in Combination With Entecavir in Patients With Chronic Hepatitis B). Dasminapant is a small molecule, second mitochondria-derived activator of caspases (SMAC)-mimetic targeting inhibitor of apoptosis proteins (IAPs) with potential apoptosis-inducing and antineoplastic activities. Upon administration, dasminapant selectively binds to and inhibits the activity of IAPs including X chromosome-linked IAP (XIAP) and cellular IAPs 1 (c-IAP1) and 2 (c-IAP2). This may restore and promote the induction of apoptosis through apoptotic signaling pathways and enhance proteasomal degradation of IAPs. Additionally, dasminapant may work synergistically with cytotoxic drugs to overcome tumor cell resistance to apoptosis. 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. |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~43.20 mM) H2O : < 0.1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.16 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (2.16 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (2.16 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8640 mL | 4.3200 mL | 8.6400 mL | |
| 5 mM | 0.1728 mL | 0.8640 mL | 1.7280 mL | |
| 10 mM | 0.0864 mL | 0.4320 mL | 0.8640 mL |