BKT140, also known as motixafortide, demonstrates specific toxicity to AmL and MM cells. Treatment with motixafortide (BKT140) prevents ARH77 MM cells from proliferating and surviving in response to IL-6. In leukemia and MM cells, motixafortide (BKT140) exclusively causes CXCR4-dependent cell death. In leukemia and MM cells, motixafortide (BKT140) induces apoptotic cell death [2].

In a dose-dependent manner, subcutaneous injection of motixafortide (BKT140) effectively inhibits the growth of human acute myeloid leukemia and multiple myeloma xenografts. Motixafortide (BKT140)-treated animals showed increased necrotic regions, decreased tumor weight and size, and higher apoptosis scores [2].

Absorption, Distribution and Excretion
Following subcutaneous injection, motixafortide Tmax ranged from 0.25 to 1.17 hours.
In animal studies in which radiolabeled motixafortide was administered, approximately 80% of the radioactive material was excreted in the urine. No parent drug was detected in the urine, and no single metabolite exceeded 30% of the total clearance.
In a typical patient, the estimated volume of distribution to the central compartment is 27 liters.
In a typical patient, the apparent total clearance of motixafortide is 46.5 L/h.

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Metabolism / Metabolites
Motixafortide is broken down via non-specific catabolic processes to smaller peptides and amino acids.

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Biological Half-Life
The effective half-life of motixafortide in human plasma is approximately 2 hours.

Protein Binding
Motixafortide is extensively (>99%) bound to human plasma proteins, although the specific protein(s) to which it may bind are unclear.

[1]. The high-affinity CXCR4 antagonist BKT140 is safe and induces a robust mobilization of human CD34+ cellsin patients with multiple myeloma. Clin Cancer Res. 2014 Jan 15;20(2):469-79.

[2]. CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth. Exp Hematol. 2011 Mar;39(3):282-92.

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.
Motixafortide is a cyclic peptide hematopoietic stem cell mobilizer used to improve stem cell collection prior to autologous transplantation. Hematopoietic stem cell transplantation (HSCT) is commonly employed in the context of hematologic cancers - high-dose chemotherapy regimens destroy cancerous blood cells, which are then replaced via infusion of the patient's own stem cells (i.e. an autologous transplant). Similar in mechanism to the previously approved [plerixafor], motixafortide is an inhibitor of C-X-C Motif Chemokine Receptor 4 (CXCR4), a protein that helps to anchor stem cells to bone marrow matrix. When administered alongside [filgrastim], another agent used to aid in stem cell collection, motixafortide enabled the collection of an adequate number of stem cells in ~92% of patients within two apheresis procedures, compared to ~26% of patients receiving only filgrastim. Motixafortide was approved by the FDA in September 2023, in combination with filgrastim, for use in stem cell mobilization prior to autologous stem cell transplant in patients with multiple myeloma. It has also been investigated alongside [pembrolizumab] for the treatment of pancreatic cancer.
Motixafortide is an orally bioavailable inhibitor of CXC Chemokine Receptor 4 (CXCR4) with potential antineoplastic activity. CXCR4 antagonist BL-8040 selectively binds to the chemokine receptor CXCR4, preventing the binding of stromal derived factor 1 (SDF-1 or CXCL12) to the CXCR4 receptor and subsequent receptor activation, which may result in decreased tumor cell proliferation and migration. In addition, inhibition of CXCR4 may induce mobilization of hematopoietic cells from the bone marrow into blood. The G protein-coupled receptor CXCR4 plays an important role in chemotaxis and angiogenesis and is upregulated in several tumor cell types; SDF-1/CXCR4 interaction induces retention of hematopoietic cells in the bone marrow.

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Drug Indication
Motixafortide is indicated for use in combination with [filgrastim] to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma.

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Mechanism of Action
Motixafortide is an inhibitor of C-X-C Motif Chemokine Receptor 4 (CXCR4) that blocks the binding of its ligand, stromal-derived factor-1α (SDF-1α)/C-X-C Motif Chemokine Ligand 12 (CXCL12). Both CXCR4 and SDF-1α play a role in the trafficking of hematopoietic stem cells to the bone marrow compartment, with CXCR4 helping to anchor stem cells to the marrow matrix (via SDF-1α or the induction of other adhesion molecules). The inhibition of CXCR4 thus results in elevations in circulating hematopoietic stem and progenitor cells into the peripheral circulation, facilitating their collection for the purposes of autologous transplantation.

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Pharmacodynamics
_In vitro_ studies have shown motixafortide to have an IC₅₀ towards CXCR4 of 0.42 – 4.5 nM, with a binding affinity and dissociation rate that allows receptor occupancy to be maintained >72 hours. In healthy volunteers administered motixafortide monotherapy, CD34+ cell counts increased over time and reached maximal levels at 16 hours postdose. In the GENESIS study, motixafortide in combination with filgrastim mobilized significantly greater CD34+ HSPC numbers within two apheresis procedures compared to filgrastim with placebo, while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs.

C97H144FN33O19S2

2159.5194

2158.074

664334-36-5

91865076

White to off-white solid powder

1.5±0.1 g/cm3

1.703

-5.95

34

28

53

152

4500

14

C1C[C@H]2C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N2C1)CCCCN)CCCCN)CCCNC(=O)N)CC3=CC=C(C=C3)O)NC(=O)[C@H](CC4=CC5=CC=CC=C5C=C4)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)C6=CC=C(C=C6)F)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N)CCCNC(=O)N)CCCNC(=N)N)CC7=CC=C(C=C7)O

JJVZSYKFCOBILL-MKMRYRNGSA-N

InChI=1S/C97H144FN33O19S2/c98-60-33-31-58(32-34-60)78(135)119-65(19-8-42-113-93(104)105)79(136)121-68(21-10-44-115-95(108)109)83(140)126-73(51-56-25-30-57-14-1-2-15-59(57)48-56)87(144)130-75-53-152-151-52-74(88(145)118-63(77(101)134)18-7-41-112-92(102)103)129-84(141)69(23-12-46-117-97(111)150)122-81(138)66(20-9-43-114-94(106)107)124-86(143)72(50-55-28-37-62(133)38-29-55)128-90(147)76-24-13-47-131(76)91(148)70(17-4-6-40-100)125-82(139)64(16-3-5-39-99)120-80(137)67(22-11-45-116-96(110)149)123-85(142)71(127-89(75)146)49-54-26-35-61(132)36-27-54/h1-2,14-15,25-38,48,63-76,132-133H,3-13,16-24,39-47,49-53,99-100H2,(H2,101,134)(H,118,145)(H,119,135)(H,120,137)(H,121,136)(H,122,138)(H,123,142)(H,124,143)(H,125,139)(H,126,140)(H,127,146)(H,128,147)(H,129,141)(H,130,144)(H4,102,103,112)(H4,104,105,113)(H4,106,107,114)(H4,108,109,115)(H3,110,116,149)(H3,111,117,150)/t63-,64-,65-,66-,67-,68-,69-,70-,71-,72-,73-,74-,75-,76-/m0/s1

(3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontine-12-carboxamide

BL8040; BL 8040; BL-8040; BKT140; BKT 140; BKT-140; TF 14016; TF14016; TF-14016; TN-14003; 4F-Benzoyl-TN14003; Aphexda.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~46.31 mM)
H2O : ~50 mg/mL (~23.15 mM)

Solubility in Formulation 1: 110 mg/mL (50.94 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)