XP-524 is a novel BET and EP300 inhibitor with anticancer activity. It is effective in endocrine-resistant ER+ breast cancer with acquired resistance to fulvestrant and palbociclib. XL-223 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated XL-223 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of XL-223 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.
Physicochemical Properties
| Molecular Formula | C30H28N6O3S |
| Molecular Weight | 552.65 |
| Exact Mass | 552.194 |
| CAS # | 2344825-52-9 |
| PubChem CID | 146036007 |
| Appearance | Light yellow to light brown solid powder |
| LogP | 2.9 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 40 |
| Complexity | 1040 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | C1=C(N=CC=C1)C(C)(C1N=CC=CC=1)N1C2C=C(C=C(C=2C=C1)NS(=O)(=O)CC)C1=CN(C)C2=C1C=CNC2=O |
| InChi Key | LMLIBNUOIWAJFC-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C30H28N6O3S/c1-4-40(38,39)34-24-17-20(23-19-35(3)28-21(23)11-15-33-29(28)37)18-25-22(24)12-16-36(25)30(2,26-9-5-7-13-31-26)27-10-6-8-14-32-27/h5-19,34H,4H2,1-3H3,(H,33,37) |
| Chemical Name | N-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indol-4-yl)ethanesulfonamide |
| Synonyms | XP223 XP-223XP 223 |
| 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
| ln Vivo | In urinePDAC, XP-524 (5 mg/kg; i.p.; given daily for 150 days) increases survival time while suppressing KRAS signaling [1]. In addition to PD-1 inhibition, XP-524 (5 mg/kg; intraperitoneal injection; administered daily for 250 days) helps prolong the survival period of KPC mice [1]. |
| Animal Protocol |
Animal/Disease Models: 15-week KPC mice [1] Doses: 5 mg/kg Route of Administration: intraperitoneal (ip) injection, daily, for 150 days Experimental Results: The mortality of KPC mice was Dramatically delayed, and the median survival period increased from 43 to 43 days after enrollment Days were extended to 108 days, and ERK activation was diminished, with a parallel decrease in cell proliferation and a uniform increase in apoptosis. Animal/Disease Models: 15-week KPC mice [1] Doses: 5 mg/kg Route of Administration: intraperitoneal (ip) injection; daily (200 μg dose of anti-PD-1 every other day) for 250 days Experimental Results: Cell-mediated cytotoxicity Increased, diminished T cell exhaustion, and the combination of XP-524 and anti-PD-1 enhanced the expression of the surrogate marker perforin-1 cytotoxicity in tumor-infiltrating CD8+ T cells. |
| References |
[1]. XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer. Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2116764119. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~33.33 mg/mL (~60.31 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.52 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 (4.52 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8095 mL | 9.0473 mL | 18.0946 mL | |
| 5 mM | 0.3619 mL | 1.8095 mL | 3.6189 mL | |
| 10 mM | 0.1809 mL | 0.9047 mL | 1.8095 mL |