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Purity: =99.62%
| Targets |
Natriuretic peptide receptor 2 (NPR2, also known as guanylyl cyclase B). Vosoritide (BMN-111) acts as an agonist of NPR2, stimulating the production of cyclic GMP (cGMP). [2]
The mechanism involves antagonizing fibroblast growth factor receptor 3 (FGFR3) downstream signaling by inhibiting the mitogen-activated protein kinase (MAPK) pathway, specifically reducing the phosphorylation of ERK1/2. [2, 3] |
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| ln Vitro |
In human growth plate chondrocytes from individuals with achondroplasia (ACH) harboring the FGFR3 c.1138G>A (p.Gly380Arg) mutation, treatment with BMN-111 (10⁻⁵ M) partially prevented the fibroblast growth factor (FGF)-mediated increase in ERK1/2 phosphorylation. This was assessed by immunoblotting of cell lysates using a phospho-ERK1/2 antibody. In contrast, FGF-mediated STAT3 phosphorylation was not decreased by BMN-111 in these cells. [3]
In chondrocytes, vosoritide (0.1 μM; 1 hour) acetate decreases NPR2 phosphorylation [2]. In cultured Fgfr3Y367C/+ femurs, voyoritide (0.1 μM; 6 days) acetate enhances chondrocyte differentiation and augments proliferative growth plate area [2]. In ACH growth plate chondrocytes, vosoritide (10 μM; overnight) acetate decreases ERK1/2 activity [3]. |
| ln Vivo |
In the Fgfr3Y367C/+ mouse model of achondroplasia, subcutaneous administration of BMN-111 led to significant recovery of bone growth. [3]
Ex Vivo (Femur Explants): In femurs isolated from E16.5 Fgfr3Y367C/+ mouse embryos, co-incubation with BMN-111 (10⁻⁶ M to 10⁻¹⁰ M) for 6 days resulted in a concentration-dependent increase in femur length. The maximum effect was observed at 10⁻⁶ M. Histological analysis showed a concentration-dependent expansion of the proliferative and hypertrophic zones, with larger and spherical hypertrophic chondrocytes, and an increased hypertrophic zone area as shown by type X collagen staining. [3] In Vivo (10-Day Treatment): Fgfr3Y367C/+ mice treated once daily with subcutaneous BMN-111 (800 μg/kg) for 10 days showed significant growth improvements, including a 5.2% increase in femur length, 5.3% increase in nasoanal length, 6.6% increase in tibia length, 4.8% increase in anterior-posterior skull diameter, and 8.0% increase in tail length compared to vehicle-treated controls (p < 0.05). Histological analysis of the distal femur revealed dose-dependent modifications, including expansion of the prehypertrophic and hypertrophic zones, with larger and more spherical hypertrophic cells. [3] In Vivo (20-Day Treatment): Extended treatment with BMN-111 (800 μg/kg once daily) for 20 days resulted in further phenotypic improvements, including flattening of the skull, elongation of the snout, improvement of the anterior crossbite, longer and straightened tibias and femurs, and longer tails. Histological analysis showed rescue of the growth plate height and architecture, with proliferative and hypertrophic chondrocytes organized in columns. [3] In mice with Fgfr3 gain-of-function mutations, vosoritide (subcutaneous injection; 800 μg/kg; once daily; 20 days) acetate therapy improves skeletal metrics [3]. |
| Cell Assay |
Western Blot Analysis (Human ACH Chondrocytes): Human control and ACH growth plate chondrocytes (harboring the FGFR3 p.Gly380Arg mutation) were isolated and cultured. Cells were pretreated with BMN-111 (10⁻⁵ M) and then co-incubated with FGF18 (100 ng/mL). Cell lysates were subjected to SDS-PAGE and hybridized overnight with a phosphorylated-ERK1/2 antibody. BMN-111 pretreatment partially prevented the FGF-mediated increase in ERK1/2 phosphorylation (n=6). STAT3 phosphorylation was assessed similarly using a phospho-STAT3 antibody, which was not decreased by BMN-111 co-incubation. [3]
Western Blot Analysis[2] Cell Types: Chondrocyte cultures Tested Concentrations: 0.1 μM Incubation Duration: 1 hour Experimental Results: Led to reduction in NPR2 phosphorylation. Western Blot Analysis[3] Cell Types: Chondrocyte Tested Concentrations: 10 μM Incubation Duration: Overnight Experimental Results: Prevented FGF-mediated increase in ERK1/2 phosphorylation. |
| Animal Protocol |
Ex Vivo Femur Culture: Femurs were dissected from E16.5 Fgfr3Y367C/+ mouse embryos and cultured in DMEM with antibiotics and 0.2% BSA for 6 days. The culture medium was supplemented with BMN-111 at concentrations ranging from 10⁻⁶ M to 10⁻¹⁰ M, or vehicle (control). The left femur was treated, and the right femur served as a control. Bone length was measured at day 0 (D0) and day 6 (D6). [3]
In Vivo Mouse Study (10-Day): Fgfr3Y367C/+ and wild-type mice (7 days old) received once-daily subcutaneous administrations of BMN-111 (240 μg/kg or 800 μg/kg) or vehicle (0.03 mol/L acetic acid buffer solution, pH 4.0, containing 1% [w/v] benzyl alcohol and 10% [w/v] sucrose) for 10 days. Dosing occurred approximately 2 hours prior to the dark cycle. Body length, tail length, and various bone segments were measured. [3] In Vivo Mouse Study (20-Day): Fgfr3Y367C/+ and wild-type mice (7 days old) received once-daily subcutaneous administrations of BMN-111 (800 μg/kg) or vehicle for 20 days. Skeletal changes were assessed by X-ray and histological analysis. [3] Animal/Disease Models: Fgfr3Y367C/+ mice[3] Doses: 800 μg/kg Route of Administration: subcutaneous (sc) injection; 800 μg/kg; one time/day; 20 days Experimental Results: Observed phenotypic changes including flattening of the skull, elongation of the snout, improvement of the anterior crossbite, larger paws and digits, and longer and straightened tibias and femurs. |
| ADME/Pharmacokinetics |
Absorption
In patients receiving daily subcutaneous injections of vosoritide 15 mcg/kg, the mean Cmax ranged from 4.71-7.18 ng/mL and the mean AUC0-t ranged from 161-290 ng-min/mL. The median Tmax following subcutaneous injection was approximately 15 minutes. Volume of Distribution The mean apparent volume of distribution following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 2880 to 3020 mL/kg. Clearance The mean apparent clearance following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 79.4 to 104 mL/min/kg. Metabolism / Metabolites As with other therapeutic proteins, vosoritide is likely metabolized via catabolic pathways into smaller peptides and amino acids. Biological Half-Life The mean half-life following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 21.0 to 27.9 minutes. BMN-111 is a 39-amino acid CNP analog designed to be resistant to neutral endopeptidase (NEP) digestion, which extends its plasma half-life compared to native CNP. This property allows for once-daily subcutaneous administration. [3] |
| Toxicity/Toxicokinetics |
In Fgfr3Y367C/+ mice treated with BMN-111 (800 μg/kg once daily) for 20 days, the tail was longer and had some kinks, suggesting a potential overdose effect, as similarly seen in mice overexpressing CNP. [3]
Hepatotoxicity In the registration studies submitted in support of approval of vosoritide, “overall, there were no clinically meaningful changes in any laboratory parameter in the clinical program.” Serum ALT levels rose to above the upper limit of normal (ULN) in 22% of vosoritide treated participants vs 18% of controls, but there were no increases above 5 times ULN or elevations accompanied by jaundice or symptoms. Alkaline phosphatase elevations arose in at least 17% of treated patients vs 7% of controls, but the abnormalities were possibly a result of bone growth rather than liver or biliary injury. In the initial clinical trial and in subsequent more widespread use of vosoritide, there have been no reports of clinically apparent liver injury or jaundice. |
| References | |
| Additional Infomation |
Achondroplasia is an autosomal dominant genetic disorder and the most common cause of dwarfism in humans. It is caused by a gain-of-function missense mutation in the FGFR3 gene, which leads to a marked suppression of bone growth, affecting both length and volume. Treatment options for achondroplasia include surgical procedures and pharmacological therapies, with the latter encompassing C-type natriuretic peptide (CNP) analogs.
Endogenous CNP, first characterized in 1998, promotes chondrocyte activity and long bone elongation primarily through its action on the NPR-B receptor, positioning it as a compelling target for treating conditions such as achondroplasia. However, the therapeutic utility of native CNP is limited by its extremely short half-life of 2 to 3 minutes, attributed to rapid degradation by endopeptidases. The development of a peptidase-resistant formulation has enabled its use as a viable treatment option.
Vosoritide is a CNP analog engineered with proline-glycine residues at its N-terminus to confer resistance to neutral endopeptidase. It was approved under the brand name Voxzogo (BioMarin Pharmaceutical Inc.) in the European Union in August 2021 and in the United States in November 2021, marking the first pharmacological intervention approved for achondroplasia in both regions.
Vosoritide is a modified recombinant C-type natriuretic peptide analog used to promote linear growth in children and adolescents with achondroplasia who still have open epiphyses. It is administered via daily subcutaneous injections. Notably, its use has not been associated with elevations in serum aminotransferase levels or with cases of clinically apparent liver injury, reflecting its favorable safety profile as a biologic analog of C-type natriuretic peptide—a potent stimulator of endochondral ossification.
Vosoritide (BMN-111) is a C-type natriuretic peptide (CNP) analog developed as a therapeutic for achondroplasia (ACH), the most common form of dwarfism, which is caused by gain-of-function mutations in FGFR3. [2, 3] The mechanism of action involves antagonizing FGFR3 downstream signaling by inhibiting the MAPK pathway, specifically reducing ERK1/2 phosphorylation. This action counteracts the negative regulation of bone growth by FGFR3. [3] In the Fgfr3Y367C/+ mouse model that recapitulates human ACH, BMN-111 treatment led to a significant recovery of bone growth, improvement in dwarfism-related clinical features (flattening of the skull, reduced crossbite, straightening of tibias and femurs), and correction of growth plate defects. [3] Phase 2 and 3 clinical trials have demonstrated that vosoritide results in a sustained increase in annualized growth velocity in children with achondroplasia. [2] Mechanism of Action: Achondroplasia is a congenital disorder caused by a missense mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a gain-of-function that negatively regulates endochondral bone formation. FGFR3 is expressed during both embryonic and postnatal development but plays distinct roles at each stage. During early development, FGFR3 signaling promotes chondrocyte proliferation (i.e., bone growth), whereas postnatal skeletal elongation is actually suppressed by FGFR3. Consequently, the pathological activation of FGFR3 observed in achondroplasia leads to impaired pre-pubertal skeletal growth. Vosoritide is an analog of C-type natriuretic peptide (CNP), a signaling molecule that is primarily responsible for stimulating chondrocyte activity and long bone elongation. When CNP (or vosoritide) binds to its cognate receptor, NPR-B, it initiates a signaling cascade that ultimately inhibits the MAPK/ERK pathway through suppression of RAF-1, thereby promoting chondrocyte proliferation and differentiation. This activity antagonizes the downstream signaling triggered by FGFR3, counteracting its inhibitory effects on bone growth. |
| Molecular Formula |
C176H290N56O51S3.C2H4O2
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|---|---|
| Molecular Weight |
4162.78
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| Exact Mass |
4148.119392
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| Related CAS # |
Vosoritide;1480724-61-5
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| PubChem CID |
176451811
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| Sequence |
Pro-Gly-Gln-Glu-His-Pro-Asn-Ala-Arg-Lys-Tyr-Lys-Gly-Ala-Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys (Disulfide bridge:Cys23-Cys39)
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| SequenceShortening |
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Disulfide bridge:Cys23-Cys39)
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
63
|
| Hydrogen Bond Acceptor Count |
67
|
| Rotatable Bond Count |
112
|
| Heavy Atom Count |
289
|
| Complexity |
9550
|
| Defined Atom Stereocenter Count |
32
|
| SMILES |
CC[C@H](C)[C@H]1C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CCCNC(=N)N)CC(=O)O)CC(C)C)CCCCN)CC(C)C)CC2=CC=CC=C2)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CC3=CC=C(C=C3)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(=N)N)NC([C@H](C)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CC5=CN=CN5)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CNC(=O)[C@@H]6CCCN6)O)C(=O)O)CC(C)C)CO)CCSC)O.CC(=O)O
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| InChi Key |
NHHKBNZICKNNGT-AXJKEOMPSA-N
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| InChi Code |
InChI=1S/C175H290N56O51S3.C2H4O2/c1-14-94(10)141-169(277)200-84-138(245)229-171(279)170(278)219-112(54-65-283-13)157(265)227-123(85-232)150(258)199-81-133(240)205-113(66-90(2)3)148(256)197-83-137(244)209-126(173(281)282)88-285-284-87-125(167(275)222-117(70-97-34-16-15-17-35-97)149(257)198-80-135(242)206-114(67-91(4)5)160(268)215-107(41-23-29-60-181)153(261)221-116(69-93(8)9)162(270)224-121(75-140(248)249)165(273)217-109(158(266)230-141)44-32-63-192-175(187)188)208-136(243)82-196-147(255)104(38-20-26-57-178)213-166(274)124(86-233)228-161(269)115(68-92(6)7)207-134(241)79-195-145(253)102(36-18-24-55-176)211-151(259)105(39-21-27-58-179)216-164(272)120(74-130(184)237)220-142(250)95(11)202-131(238)77-194-146(254)103(37-19-25-56-177)212-163(271)118(71-98-46-48-100(234)49-47-98)223-154(262)106(40-22-28-59-180)214-152(260)108(43-31-62-191-174(185)186)210-143(251)96(12)203-159(267)119(73-129(183)236)225-168(276)127-45-33-64-231(127)172(280)122(72-99-76-189-89-201-99)226-156(264)111(51-53-139(246)247)218-155(263)110(50-52-128(182)235)204-132(239)78-193-144(252)101-42-30-61-190-101;1-2(3)4/h15-17,34-35,46-49,76,89-96,101-127,141,143,171,190,210,232-234,251,279H,14,18-33,36-45,50-75,77-88,176-181H2,1-13H3,(H2,182,235)(H2,183,236)(H2,184,237)(H,189,201)(H,193,252)(H,194,254)(H,195,253)(H,196,255)(H,197,256)(H,198,257)(H,199,258)(H,200,277)(H,202,238)(H,203,267)(H,204,239)(H,205,240)(H,206,242)(H,207,241)(H,208,243)(H,209,244)(H,211,259)(H,212,271)(H,213,274)(H,214,260)(H,215,268)(H,216,272)(H,217,273)(H,218,263)(H,219,278)(H,220,250)(H,221,261)(H,222,275)(H,223,262)(H,224,270)(H,225,276)(H,226,264)(H,227,265)(H,228,269)(H,229,245)(H,230,266)(H,246,247)(H,248,249)(H,281,282)(H4,185,186,191)(H4,187,188,192);1H3,(H,3,4)/t94-,95-,96-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,141-,143?,171-;/m0./s1
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| Chemical Name |
acetic acid;(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-5-oxo-2-[[2-[[(2S)-pyrrolidine-2-carbonyl]amino]acetyl]amino]pentanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]-1-hydroxypropyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]acetyl]amino]-40-(4-aminobutyl)-49-benzyl-28-[(2S)-butan-2-yl]-31-(3-carbamimidamidopropyl)-34-(carboxymethyl)-22-hydroxy-16-(hydroxymethyl)-10,37,43-tris(2-methylpropyl)-19-(2-methylsulfanylethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecazacyclotripentacontane-4-carboxylic acid
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| Synonyms |
Vosoritide; Voxzogo; BMN-111 acetate; 1480724-61-5; BMN 111 acetate;
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| HS Tariff Code |
2934.99.9001
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| Storage |
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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O :≥ 100 mg/mL (~24.02 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2402 mL | 1.2011 mL | 2.4022 mL | |
| 5 mM | 0.0480 mL | 0.2402 mL | 0.4804 mL | |
| 10 mM | 0.0240 mL | 0.1201 mL | 0.2402 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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