Repositioning Candidate Details

Candidate ID: R1608
Source ID: DB16703
Source Type: approved; investigational
Compound Type: small molecule
Compound Name: Belumosudil
Synonyms: Belumosudil
Molecular Formula: C26H24N6O2
SMILES: CC(C)NC(=O)COC1=CC=CC(=C1)C1=NC2=C(C=CC=C2)C(NC2=CC=C3NN=CC3=C2)=N1
Structure:
DrugBank Description: Belumosudil is used in the treatment of chronic graft-versus-host disease (GVHD) and has been investigated for the treatment of pulmonary arterial hypertension. It is an inhibitor of rho-associated coiled-coil-containing protein kinases (ROCK), with significantly more selectivity for ROCK2 as compared to ROCK1 (IC<sub>50</sub> 100 nM vs. 3 μM, respectively). In the treatment of GVHD, a condition in which donor T-cells begin to attack recipient tissues following allogeneic hematopoeitic stem cell transplantation (HSCT), belumosudil helps to resolve immune dysregulation by shifting the balance between Th17 cells and T-regulatory cells, thereby dampening the inflammatory cascade that can occasionally be fatal. Belumosudil was first approved by the FDA in July 2021, under the brand name Rezurock, for the treatment of chronic GVHD in patients who have tried and failed at least two prior lines of systemic therapy.
CAS Number: 911417-87-3
Molecular Weight: 452.518
DrugBank Indication: Belumosudil is indicated for the treatment of chronic graft-versus-host disease (GVHD) in adult and pediatric patients 12 years of age and older following failure of at least two other lines of systemic therapy.
DrugBank Pharmacology: Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed. Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose.
DrugBank MoA: Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response. During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses. Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5.
Targets: Rho-associated protein kinase 2 inhibitor; Rho-associated protein kinase 1 inhibitor
Inclusion Criteria: Therapeutic strategy associated