Chemistry:Belumosudil
 | |
| Clinical data | |
|---|---|
| Routes of administration | Oral administration (tablets or capsules) |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| UNII | |
| Chemical and physical data | |
| Formula | C26H24N6O2 |
| Molar mass | 452.518 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Belumosudil (formerly KD025 and SLx-2119) is an experimental drug being explored for the treatment of chronic graft versus host disease (cGvHD), idiopathic pulmonary fibrosis (IPF), and moderate to severe psoriasis. It is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2; ROCK-II).[1] Belumosudil binds to and inhibits the serine/threonine kinase activity of ROCK2. This inhibits ROCK2-mediated signaling pathways which play major roles in pro- and anti-inflammatory immune cell responses. A genomic study in human primary cells demonstrated that the drug also has effects on oxidative phosphorylation, WNT signaling, angiogenesis, and KRAS signaling.[2] Originally developed by Surface Logix, Inc,[1] Belumosudil was later acquired by Kadmon Corporation. As of July 2020 the drug was in completed or ongoing Phase II clinical studies for cGvHD, IPF and psoriasis.[3]
cGvHD is a complication that can follow stem cell or hematopoietic stem cell transplantation where the transplanted cells (graft) attack healthy cells (host). This causes inflammation and fibrosis in multiple tissues. Two cytokines controlled by the ROCK2 signaling pathway, IL-17 and IL-21, have a major role in the cGvHD response. In a 2016 report using both mouse models and a limited human clinical trial ROCK2 inhibition with belumosudil targeted both the immunologic and fibrotic components of cGvHD and reversed the symptoms of the disease.[4] In October 2017 KD025 was granted orphan drug status in the United States for treatment of patients with cGvHD.[5]
IPF is a progressive fibrotic disease where the lining of the lungs become thickened and scarred.[6] Increased ROCK activity has been found in the lungs of humans and animals with IPF. Treatment with belumosudil reduced lung fibrosis in a bleomycin mouse model study.[7] Belumosudil may have a therapeutic benefit in IPF by targeting the fibrotic processes mediated by the ROCK signaling pathway.
Psoriasis is an inflammatory skin condition where patients experiences eruptions and remissions of thickened, erythematous, and scaly patches of skin. Down-regulation of pro-inflammatory responses was observed with KD025 treatment in Phase 2 clinical studies in patients with moderate to severe psoriasis.[8]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
"Substance Name:Substance Name: Belumosudil [USAN"]. US National Library of Medicine. https://chem.nlm.nih.gov/chemidplus/rn/911417-87-3.
References
- ↑ 1.0 1.1 "Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin". Blood Coagulation & Fibrinolysis 19 (7): 709–18. October 2008. doi:10.1097/MBC.0b013e32830b2891. PMID 18832915.
- ↑ "Identification of novel functions of the ROCK2-specific inhibitor KD025 by bioinformatics analysis.". Gene 737: 144474. 5 May 2020. doi:10.1016/j.gene.2020.144474. PMID 32057928.
- ↑ "KD025 - Clinical Trials". ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=&term=KD025+Phase+2&cntry=&state=&city=&dist=.
- ↑ "Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism". Blood 127 (17): 2144–54. April 2016. doi:10.1182/blood-2015-10-678706. PMID 26983850.
- ↑ Shanley, Mathew (October 6, 2017). "Therapy to Treat Transplant Complications Gets Orphan Drug Designation". https://www.raredr.com/news/kd025-orphan-drug-designation/.
- ↑ "Pulmonary Fibrosis". The Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/pulmonary-fibrosis/symptoms-causes/syc-20353690.
- ↑ Semedo, Daniela (June 5, 2016). "Phase 2 Study of Molecule Inhibitor for Idiopathic Pulmonary Fibrosis Begins". BioNews Services, LLC. https://lungdiseasenews.com/2016/06/05/kadmon-initiates-phase-2-clinical-trial-evaluating-kd025-idiopathic-pulmonary-fibrosis/.
- ↑ "Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10". Journal of Immunology 198 (10): 3809–3814. May 2017. doi:10.4049/jimmunol.1602142. PMID 28389592.
 |  |
