AMG-176 (AMG176; tapotoclax) is a novel, potent, selective and orally bioavailable inhibitor of MCL-1 (myeloid cell leukemia-1) with a Ki of 0.13 nM. Potential pro-apoptotic and anti-cancer effects of AMG-176 exist. MCL-1 is bound by AMG 176, which then stops it from working. This causes apoptosis in tumor cells and interferes with the formation of MCL-1/Bcl-2-like protein 11 (BCL2L11; BIM) complexes. The Bcl-2 family of proteins member MCL-1, an anti-apoptotic protein, is upregulated in cancer cells and supports the survival of tumor cells.
Physicochemical Properties
| Molecular Formula | C33H41CLN2O5S |
| Molecular Weight | 613.207047224045 |
| Exact Mass | 612.24 |
| Elemental Analysis | C, 64.64; H, 6.74; Cl, 5.78; N, 4.57; O, 13.05; S, 5.23 |
| CAS # | 1883727-34-1 |
| Related CAS # | 1883727-34-1 |
| PubChem CID | 118910268 |
| Appearance | White to off-white solid powder |
| LogP | 6.8 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 1 |
| Heavy Atom Count | 42 |
| Complexity | 1110 |
| Defined Atom Stereocenter Count | 6 |
| SMILES | C[C@H]1C/C=C/[C@@H]([C@@H]2CC[C@H]2CN3C[C@@]4(CCCC5=C4C=CC(=C5)Cl)COC6=C3C=C(C=C6)C(=O)NS(=O)(=O)[C@@H]1C)OC |
| InChi Key | JQNINBDKGLWYMU-GEAQBIRJSA-N |
| InChi Code | InChI=1S/C33H41ClN2O5S/c1-21-6-4-8-30(40-3)27-12-9-25(27)18-36-19-33(15-5-7-23-16-26(34)11-13-28(23)33)20-41-31-14-10-24(17-29(31)36)32(37)35-42(38,39)22(21)2/h4,8,10-11,13-14,16-17,21-22,25,27,30H,5-7,9,12,15,18-20H2,1-3H3,(H,35,37)/b8-4+/t21-,22+,25-,27+,30-,33-/m0/s1 |
| Chemical Name | (3'R,4S,6'R,7'S,8'E,11'S,12'R)-7-chloro-7'-methoxy-11',12'-dimethyl-13',13'-dioxospiro[2,3-dihydro-1H-naphthalene-4,22'-20-oxa-13lambda6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15'-one |
| Synonyms | tapotoclaxum; tapotoclax; AMG-176; AMG176; AMG 176 |
| 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 |
| 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
| Targets | Mcl-1 (Ki = 0.13 nM) |
| ln Vitro | Tapoclax is a compound that has the ability to stimulate cell color development and anti-tumor action. It also promotes the production of MCL-1 (Ki=0.13 nM) in inducible myeloid leukemia cells. After then, tapotoclax attaches to MCL-1 and prevents its function. It stimulates tumor cells and interferes with the formation of the MCL-1/Bcl-2-like protein 11 (BCL2L11; BIM) complex [1][2]. |
| References |
[1]. AMG 176, a Selective MCL1 Inhibitor, is Effective in Hematological Cancer Models Alone and in Combination with Established Therapies. Cancer Discov. 2018 Sep 25. pii: CD-18-0387. [2]. Progress in targeting the BCL-2 family of proteins. Curr Opin Chem Biol. 2017 Aug;39:133-142. |
| Additional Infomation |
Tapotoclax is an inhibitor of induced myeloid leukemia cell differentiation protein MCL-1 (myeloid cell leukemia-1), with potential pro-apoptotic and antineoplastic activities. Upon administration, tapotoclax binds to and inhibits the activity of MCL-1. This disrupts the formation of MCL-1/Bcl-2-like protein 11 (BCL2L11; BIM) complexes and induces apoptosis in tumor cells. MCL-1, an anti-apoptotic protein belonging to the Bcl-2 family of proteins, is upregulated in cancer cells and promotes tumor cell survival. Drug Indication Treatment of acute myeloid leukaemia |
Solubility Data
| Solubility (In Vitro) | DMSO: ~62.5 mg/mL (~101.9 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2 mg/mL (3.26 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 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 mg/mL (3.26 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 20.0 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 mg/mL (3.26 mM) in 10% DMSO + 90% Corn Oil (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 20.0 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 | 1.6308 mL | 8.1538 mL | 16.3076 mL | |
| 5 mM | 0.3262 mL | 1.6308 mL | 3.2615 mL | |
| 10 mM | 0.1631 mL | 0.8154 mL | 1.6308 mL |