| Size | Price | Stock | Qty |
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| Targets |
TrkA
TRK (tropomyosin receptor kinase) family: TrkA, TrkB, and TrkC (encoded by NTRK1, NTRK2, NTRK3). Paltimatrectinib is a pan-TRK inhibitor that targets and binds to TRKs, including mutated TRKs and fusion proteins. |
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| ln Vitro |
Paltimatrectinib specifically inhibits the activity of TRK fusion proteins. By blocking the TRK signaling pathway, it prevents the activation of downstream targets, leading to the induction of cellular apoptosis and the inhibition of cell growth in TRK-dependent tumors. It has shown high potency in preclinical assays.
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| ln Vivo |
Preclinical data demonstrate robust efficacy in animal models of TRK-driven cancers, including intracranial models, due to its high brain penetration. As a pan-TRK inhibitor, it is effective against tumors that have developed resistance to first-generation TRK inhibitors. Paltimatrectinib is currently in Phase 1/2 clinical trials.
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| Enzyme Assay |
Cell-free TRK kinase assays are performed using recombinant TRKA, TRKB, and TRKC enzymes. The compound is incubated with the enzyme, a substrate, and [gamma-33P]-ATP. The reaction is stopped, and the incorporated radioactivity is measured to determine the IC50. Alternatively, a time-resolved fluorescence (TR-FRET) assay can be used.
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| Cell Assay |
TRK fusion-positive cell lines (e.g., KM-12 colorectal cancer cells with TPM3-NTRK1) are seeded in 96-well plates. After 24 hours, they are treated with serial dilutions of paltimatrectinib for 72 hours. Cell viability is measured using the CellTiter-Glo reagent. The half-maximal inhibitory concentration (IC50) is calculated by nonlinear regression.
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| Animal Protocol |
For in vivo efficacy studies, nude mice are implanted subcutaneously with TRK fusion-positive cancer cells. Once tumors reach a certain size, mice are randomized and treated orally with paltimatrectinib. Tumor volumes are measured with calipers. For brain penetration studies, mice are dosed, and brain and plasma concentrations are analyzed by LC-MS/MS.
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| ADME/Pharmacokinetics |
Paltimatrectinib is designed to be an orally bioavailable, brain-penetrant small molecule. It has favorable ADME properties that allow it to cross the blood-brain barrier effectively, which is critical for treating brain metastases common in NTRK fusion-positive cancers. The half-life supports once- or twice-daily dosing.
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| Toxicity/Toxicokinetics |
No specific toxicity data are publicly detailed, but as a TRK inhibitor, the primary risks include sensory neuropathy and weight gain, which are on-target class effects. Preclinical toxicology studies have likely shown a manageable safety profile, which is being confirmed in ongoing Phase 1/2 clinical trials (NCT04901806).
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| References | |
| Additional Infomation |
Paltimatrectinib is a highly bioavailable, blood-brain barrier-crossing pantropomyosin-associated kinase (tyrosine receptor kinase; TRK) inhibitor with potential antitumor activity. After oral administration, Paltimatrectinib specifically targets and binds to TRK, mutant TRK, and fusion proteins containing sequences of neurotrophic tyrosine receptor kinases (NTRK) type 1 (NTRK1; TrkA), type 2 (NTRK2; TrkB), and type 3 (NTRK3; TrkC). This inhibits the interaction between neurotrophic factors and TRK, as well as TRK activation, thereby preventing the activation of downstream signaling pathways and ultimately leading to apoptosis and growth inhibition in tumor cells with TRK overexpression and/or NTRK fusion protein expression. TRKs are a class of receptor tyrosine kinases (RTKs) activated by neurotrophic factors and encoded by NTRK family genes. Mutant forms of NTRK family members or the expression of fusion proteins lead to uncontrolled TRK signaling, which plays a crucial role in tumor cell growth, survival, invasion, and treatment resistance.
Other information: Paltimatrectinib is a novel Pan-TRK inhibitor that may be Pyramid Biosciences' clinical candidate, PBI-200. The use of the '-trectinib' stem in its name confirms it as a TRK inhibitor. It has a molecular weight of 434.4 g/mol and CAS number 2353522-15-1. It is currently in Phase II clinical trials. |
| Molecular Formula |
C20H15F5N6
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|---|---|
| Molecular Weight |
434.365320444107
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| Exact Mass |
434.127
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| Elemental Analysis |
C, 55.30; H, 3.48; F, 21.87; N, 19.35
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| CAS # |
2353522-15-1
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| PubChem CID |
155753054
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| Appearance |
Off-white to yellow solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
31
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| Complexity |
638
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C=CC(=CC=1[C@H]1CCCN1C1C=CN2C(=C(C=N2)N2C=C(C(F)(F)F)C=N2)N=1)F
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| InChi Key |
FYPXPQSPRRZJCK-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C20H15F5N6/c21-13-3-4-15(22)14(8-13)16-2-1-6-29(16)18-5-7-30-19(28-18)17(10-27-30)31-11-12(9-26-31)20(23,24)25/h3-5,7-11,16H,1-2,6H2/t16-/m1/s1
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| Chemical Name |
5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-[4-(trifluoromethyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine
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| Synonyms |
Paltimatrectinib; PBI-200; PPI5278; PBI200; PPI-5278; 2353522-15-1; PBI 200; PPI 5278; Paltimatrectinib [INN]; SP4MKH8Y5J; 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-[4-(trifluoromethyl)pyrazol-1-yl]pyrazolo[1,5-a]pyrimidine;
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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 |
| 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) |
DMSO: 25 mg/mL (57.55 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 | 2.3022 mL | 11.5109 mL | 23.0218 mL | |
| 5 mM | 0.4604 mL | 2.3022 mL | 4.6044 mL | |
| 10 mM | 0.2302 mL | 1.1511 mL | 2.3022 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04901806
Conditions:Solid Tumor, Adult|Brain Tumor, Primary|Desmoplastic Small Round Cell TumorLink: https://clinicaltrials.gov/ct2/show/NCT05690932
Conditions:Formulation Bridging|Food EffectLink: https://clinicaltrials.gov/ct2/show/NCT05692570
Conditions:Drug-drug Interaction
Title:A Study to Assess the Effect of Food on the Absorption and Bioavailability of PBI-200
Status:Completed
updateDate:2022-01-27
Ctid:NCT05160389
Link: https://clinicaltrials.gov/ct2/show/NCT05160389
Conditions:Food Effect in Healthy VolunteersProducts are for research use only; We do not sell to patients
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