Bemcentinib

Bemcentinib
Clinical data
Other names	BGB324; R428
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name 1-(6,7-Dihydro-5H-benzo[2,3]cyclohepta[2,4-d]pyridazin-3-yl)-3-N-[(7S)-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1,2,4-triazole-3,5-diamine;
CAS Number	1037624-75-1;
PubChem CID	46215462;
UNII	0ICW2LX8AS;
KEGG	D11438;
CompTox Dashboard (EPA)	DTXSID70673109 ;
Chemical and physical data
Formula	C30H34N8
Molar mass	506.658 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Nc1nc(Nc2ccc3c(c2)CC[C@H](N2CCCC2)CC3)nn1-c1cc2c(nn1)-c1ccccc1CCC2;
	InChI InChI=1S/C30H34N8/c31-29-33-30(32-24-13-10-20-11-14-25(15-12-22(20)18-24)37-16-3-4-17-37)36-38(29)27-19-23-8-5-7-21-6-1-2-9-26(21)28(23)35-34-27/h1-2,6,9-10,13,18-19,25H,3-5,7-8,11-12,14-17H2,(H3,31,32,33,36)/t25-/m1/s1; Key:KXMZDGSRSGHMMK-RUZDIDTESA-N;

Bemcentinib, also known as BGB324 or R428, is an experimental oral small molecule that is an inhibitor of AXL kinase.^[1] Bemcentinib was licensed from Rigel Pharmaceuticals by BerGenBio and currently undergoing six Phase II trials in various solid and hematological tumors as monotherapy and in combination with immunotherapy, chemotherapy, and targeted therapeutics.

Function

Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumor cells, leading to aggressive metastatic cancers.^[2] In addition, BGB324 enhances sensitivity to various therapies including chemotherapy, immunotherapy and several targeted therapeutics.^[3]^[4]

Clinical trials

Bemcentinib is currently undergoing Phase II clinical trials for non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), acute myeloid leukemia /myelodysplastic syndrome (AML/MDS), melanoma and metastatic pancreatic cancer.^{[citation needed]}

COVID-19

In April 2020 Bemcentinib became the first candidate to be selected as part of the UK Government's ACCORD (Accelerating COVID-19 Research & Development) for Phase II clinical trial in patients with COVID-19.^[5]

References

^ "Definition of AXL inhibitor BGB324". NCI Drug Dictionary. National Cancer Institute. 2011-02-02.
^ Gay, Carl M; Balaji, Kavitha; Byers, Lauren Averett (2017). "Giving AXL the axe: targeting AXL in human malignancy". British Journal of Cancer. 116 (4): 415–423.
^ Davidsen KT, Haaland GS, Lie MK, Lorens JB, Engelsen AS (2017). "The role of Axl receptor tyrosine kinase in tumor cell plasticity and therapy resistance.". In Akslen L, Watnick R (eds.). Biomarkers of the Tumor Microenvironment. Springer, Cham. pp. 351–376.
^ Oien DB, Garay T, Eckstein S, Chien J (2018). "Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy". Frontiers in Pharmacology. 8: 970. doi:10.3389/fphar.2017.00970. PMC 5768913. PMID 29375377.
^ "BerGenBio's Bemcentinib Selected to be Fast-tracked as Potential Treatment for COVID-19 Through New National UK Government Clinical Trial Initiative". Cision. Retrieved 29 April 2020.

[1] "Definition of AXL inhibitor BGB324". NCI Drug Dictionary. National Cancer Institute. 2011-02-02.

[2] Gay, Carl M; Balaji, Kavitha; Byers, Lauren Averett (2017). "Giving AXL the axe: targeting AXL in human malignancy". British Journal of Cancer. 116 (4): 415–423.

[3] Davidsen KT, Haaland GS, Lie MK, Lorens JB, Engelsen AS (2017). "The role of Axl receptor tyrosine kinase in tumor cell plasticity and therapy resistance.". In Akslen L, Watnick R (eds.). Biomarkers of the Tumor Microenvironment. Springer, Cham. pp. 351–376.

[4] Oien DB, Garay T, Eckstein S, Chien J (2018). "Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy". Frontiers in Pharmacology. 8: 970. doi:10.3389/fphar.2017.00970. PMC 5768913. PMID 29375377.

[5] "BerGenBio's Bemcentinib Selected to be Fast-tracked as Potential Treatment for COVID-19 Through New National UK Government Clinical Trial Initiative". Cision. Retrieved 29 April 2020.

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