| Identification | Back Directory | [Name]
HRX-0215 | [CAS]
2369583-33-3 | [Synonyms]
HRX215
HRX-0215
Darizmetinib
N-[2,6-Difluoro-3-[[5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]carbonyl]phenyl]-1-propanesulfonamide | [Molecular Formula]
C21H17F2N5O3S | [MOL File]
2369583-33-3.mol | [Molecular Weight]
457.46 |
| Chemical Properties | Back Directory | [Boiling point ]
689.9±65.0 °C(Predicted) | [density ]
1.490±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted) | [form ]
Solid | [pka]
6.03±0.10(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
HRX-0215 is a small molecule inhibitor of Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4), a key regulator of liver regeneration. Suppression of MKK4 unlocks the regenerative capacity of hepatocytes even in severely diseased livers. | [Uses]
Darizmetinib (HRX-0215) is an orally active, potent and selective inhibitor of mitogen-activated protein kinase kinase 4 (MKK4). Darizmetinib leads to enhancement of the MKK7 and JNK1 signaling pathways, thereby activating the transcription factors ATF2 and ELK1, promoting cell proliferation and liver regeneration. Darizmetinib is promising for research of preventing liver failure after extensive oncological liver resections or transplantation of small liver grafts[1][2][3]. | [in vivo]
Darizmetinib (30 mg/kg, p.o., a single dose for 15 min-24 h) increases the number of proliferating hepatocytes upon partial hepatectomy in fibrotic mouse livers [3].
Darizmetinib (10 mg/kg, p.o., a single dose for 2 h and 9 h) activates pro-regenerative program by increaseing MKK7 and JNK1 signaling with a downstream activation of the transcription factors ATF2 and ELK1, reduces p38- and p53 activation, activates nuclear factor κB (NF-κB) signaling, and upregulates the anti-apoptotic protein Bcl-XL in hepatectomized mice[3].
Darizmetinib (5 mg/kg, i.v., every 12 h, starting 24 h before surgery)--mediated suppression of MKK4 increases hepatocyte regeneration in a pig hepatectomy model[3].
| Animal Model: | partial hepatectomy in fibrotic mouse livers[2] | | Dosage: | 30 mg/kg | | Administration: | p.o., a single dose for 15 min-24 h | | Result: | Enhanced hepatocyte proliferation in partial hepatectomy in fibrotic mouse livers, suggesting that the presence of fibrosis per se does not interfere with the Darizmetinib-mediated pro-regenerative mechanism. |
| [References]
[1] Praefke B, et al. Preparation of pyrazolopyridines as protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death: World Intellectual Property Organization, WO2019149738. 2019-08-08.
[2] WHO Drug Information-World Health Organization (WHO).
[3] Zwirner S, et al. First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure. Cell. 2024 Mar 28;187(7):1666-1684.e26. DOI:10.1016/j.cell.2024.02.023 |
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