WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H573175
CAS#: 2064292-12-0
Description: A1874 is a nutlin-based and BRD4-degrading PROTAC which induces BRD4 degradation in cells.
Hodoodo Cat#: H573175
Name: A1874
CAS#: 2064292-12-0
Chemical Formula: C58H62Cl3F2N9O7S
Exact Mass: 1,171.35
Molecular Weight: 1,173.600
Elemental Analysis: C, 59.36; H, 5.33; Cl, 9.06; F, 3.24; N, 10.74; O, 9.54; S, 2.73
Synonym: A1874, A-1874; A 1874;
IUPAC/Chemical Name: (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-((1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamoyl)-2-methoxyphenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide
InChi Key: IPNTVOAQOGRLQB-JJMBTQCASA-N
InChi Code: InChI=1S/C58H62Cl3F2N9O7S/c1-32-33(2)80-56-48(32)51(35-11-14-37(59)15-12-35)67-44(53-71-70-34(3)72(53)56)29-47(73)65-19-21-77-23-25-79-26-24-78-22-20-66-54(74)36-13-18-43(45(27-36)76-7)68-55(75)52-49(39-9-8-10-41(61)50(39)63)58(31-64,46(69-52)30-57(4,5)6)40-17-16-38(60)28-42(40)62/h8-18,27-28,44,46,49,52,69H,19-26,29-30H2,1-7H3,(H,65,73)(H,66,74)(H,68,75)/t44-,46-,49-,52+,58-/m0/s1
SMILES Code: O=C([C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(C2=CC=C(Cl)C=C2F)[C@H]1C3=CC=CC(Cl)=C3F)NC4=CC=C(C(NCCOCCOCCOCCNC(C[C@H]5C6=NN=C(C)N6C7=C(C(C)=C(C)S7)C(C8=CC=C(Cl)C=C8)=N5)=O)=O)C=C4OC
Appearance: 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
Shelf Life: >3 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:
| Biological target: | A1874 is a nutlin-based and BRD4-degrading PROTAC with a DC50 of 32 nM (induce BRD4 degradation in cells). |
| In vitro activity: | Suppression of c-Myc or induction of p21CIP1/WAF1 -- either one alone -- will inhibit cell proliferation. HCT116 cells incubated with JQ1 or idasanutlin for 48h showed clear dose-dependent loss of viability (Figure 3A). Treatment with JQ1 resulted in 25% loss of MTS signal compared to control cells; and idasanutlin treatment caused a 62% loss. However, treatment with A1874, which combines the activities of the two inhibitors, ultimately resulted in a 97% loss in HCT116 cell viability. That the effect of A1874 was greater than either idasanutlin or JQ1 alone, and even slightly more effective than a combined treatment (Supplementary Figure S1), demonstrates that combining both activities into a single PROTAC does not result in one activity diminishing the other. Reference: Cancer Res. 2019 Jan 1; 79(1): 251–262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318015/ |
| In vivo activity: | By recording tumor growth curve, this demonstrated that A1874 oral administration (20 mg/kg, daily, 21 days) potently inhibited colon cancer xenograft growth in SCID mice (Fig. 5a). Calculating the estimated daily tumor growth, using the formula: (Tumor volume at D42—Tumor volume at D0)/42 (days), this study found that colon cancer xenograft growth was largely inhibited in A1874-treated mice (Fig. 5b). Tumors from the two groups were isolated and weighted individually at experimental Day-42 (D42). Xenograft tumors with A1874 administration were significantly lighter than those of vehicle control mice (Fig. 5c). Mouse body weights were not significantly different between A1874-treated and vehicle control mice (Fig. 5d), and no noticeable toxicity was observed in the mice. These results show that oral administration of A1874 is able to inhibit colon cancer xenograft growth in SCID mice. Reference: Cell Death Dis. 2020 Sep; 11(9): 805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519683/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 125.0 | 106.51 | |
| Ethanol | 100.0 | 85.21 |
The following data is based on the product molecular weight 1,173.60 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 |
| Formulation protocol: | 1. Qin AC, Jin H, Song Y, Gao Y, Chen YF, Zhou LN, Wang SS, Lu XS. The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells. Cell Death Dis. 2020 Sep 25;11(9):805. doi: 10.1038/s41419-020-03015-6. PMID: 32978368; PMCID: PMC7519683. 2. Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53. Cancer Res. 2019 Jan 1;79(1):251-262. doi: 10.1158/0008-5472.CAN-18-2918. Epub 2018 Nov 1. PMID: 30385614; PMCID: PMC6318015. |
| In vitro protocol: | 1. Qin AC, Jin H, Song Y, Gao Y, Chen YF, Zhou LN, Wang SS, Lu XS. The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells. Cell Death Dis. 2020 Sep 25;11(9):805. doi: 10.1038/s41419-020-03015-6. PMID: 32978368; PMCID: PMC7519683. 2. Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53. Cancer Res. 2019 Jan 1;79(1):251-262. doi: 10.1158/0008-5472.CAN-18-2918. Epub 2018 Nov 1. PMID: 30385614; PMCID: PMC6318015. |
| In vivo protocol: | 1. Qin AC, Jin H, Song Y, Gao Y, Chen YF, Zhou LN, Wang SS, Lu XS. The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells. Cell Death Dis. 2020 Sep 25;11(9):805. doi: 10.1038/s41419-020-03015-6. PMID: 32978368; PMCID: PMC7519683. |
1: Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-recruiting PROTAC Offers Superior, Synergistic Anti-proliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53. Cancer Res. 2018 Nov 1. pii: canres.2918.2018. doi: 10.1158/0008-5472.CAN-18-2918. [Epub ahead of print] PubMed PMID: 30385614.
