BL-8040

Uses

BKT140 is a CXCR4 inhibitor with potential antineoplastic activity. BKT140 is also a safe and efficient stem cell mobilizer for engraftment.

Definition

ChEBI: Motixafortide is a heterodetic cyclic peptide that has antineoplastic activity. It is a CXC chemokine receptor 4 (CXCR4) antagonist with an IC50 value of 0.8 nM and is currently under clinical investigation for the treatment of hematological malignancies, solid tumors, and stem cell mobilization. It was granted orphan drug designation by the FDA for the treatment of pancreatic cancer in 2019. It has a role as an apoptosis inducer, an antineoplastic agent and a C-X-C chemokine receptor type 4 antagonist.

Biological Activity

bkt140, also known as bl-8040 and tf 14016, is an orally bioavailable inhibitor of cxc chemokine receptor 4 (cxcr4) with potential antineoplastic activity [1].the g protein-coupled receptor cxcr4 plays an important role in chemotaxis and angiogenesis and is upregulated in several tumor cell types. cxcr4 has been involved in promoting tumor progression. cxcr4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. cxcr4 acts as an important molecule involved in the spread and progression of a variety of different tumors [2].bkt140 reduced the colony-forming capacity of non-small cell lung cancer (nsclc) cells. subcutaneous administration of bkt140 significantly delayed the development of h460 xenografts and showed a similar trend for a549 xenografts [1]. pre-clinical studies in animal models with bkt140 showed a robust mobilization of white blood cells (wbc) and hematopoietic stem cells (hsc). bkt140 showed a direct anti-tumor effect against human-derived multiple myeloma (mm), lymphoma and primary leukemia cells and cell lines in vitro and in vivo, causing significant apoptosis [2]. bkt140 was well tolerated and rapidly absorbed in patients with multiple myeloma. bkt140 administration significantly increased the number of peripheral blood neutrophils, monocytes, lymphocytes, and cd34+ cells in a dose-dependent manner [3].

Enzyme inhibitor

This orally bioavailable, disulfide cross-linked, polyphemusin-II-derived peptide antagonist (sequence shown above, with Nal = naphthylamine, Cit = citrulline, D-Lys = D-Lysine, and Cys = half-cystine), also known as 4-Fbenzoyl-TN14003 and BL-8040, targets CXC Chemokine Receptor-4 (CXCR4), a G-protein-coupled receptor that is directly involved in tumor progression, tumor angiogenesis, metastasis, and cancer cell survival. Primary Mode of Inhibitory Action: CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. BKT140 exhibits high affinity (Ki = 0.8nM) and a low rate of dissociation from its receptor. BKT140 prevents the binding of stromal derived factor-1 (SDF-1 or CXCL12) to CXCR4 activation, resulting in decreased tumor cell proliferation and migration. In addition, inhibition of CXCR4 may mobilize hematopoietic cell egress from the bone marrow and into blood. BKT140 significantly and preferentially stimulates multiple myeloma apoptotic cell death, as indicated by induced morphological changes, phosphatidylserine externalization, decreased mitochondrial membrane potential, caspase-3 activation, sub-G1 cell-cycle arrest, as well as DNA double-stranded breaks.

References

[1] fahham d, weiss i d, abraham m, et al. in vitro and in vivo therapeutic efficacy of cxcr4 antagonist bkt140 against human non–small cell lung cancer[j]. the journal of thoracic and cardiovascular surgery, 2012, 144(5): 1167-1175. e1.
[2] burger j a, kipps t j. cxcr4: a key receptor in the crosstalk between tumor cells and their microenvironment[j]. blood, 2006, 107(5): 1761-1767.
[3] nagler a, shimoni a, avivi i, et al. bkt140 is a novel cxcr4 antagonist with stem cell mobilization and antimyeloma effects: an open-label first human trial in patients with multiple myeloma undergoing stem cell mobilization for autologous transplantation[j]. blood, 2010, 116(21): 2260-2260.