| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
Tubulin (microtubule) [1].
The compound binds at the interface of α,β-tubulin heterodimer, adjacent to the vinca binding site, and inhibits tubulin polymerization [1]. PF-06380101 targets tubulin, a key component of the microtubule cytoskeleton. As a microtubule inhibitor, PF-06380101 binds to tubulin and disrupts microtubule dynamics, which are essential for cell division, intracellular transport, and maintenance of cell shape. By inhibiting microtubule polymerization or promoting depolymerization, the compound arrests cells in mitosis and induces apoptosis. PF-06380101 is a cytotoxic Dolastatin 10 analogue, belonging to the auristatin class of microtubule inhibitors. Auristatins are potent anti-tubulin agents that have been widely used as payloads in antibody-drug conjugates (ADCs) for targeted cancer therapy. |
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| ln Vitro |
PF-06380101 demonstrated a mean systemic clearance (Cl) of 70 mL/min/kg and a volume of distribution (Vss) of 14.70 L/kg following an IV dose of 20a at 20 μg/kg to Wistar Han rats. This led to an approximate 6-hour terminal elimination half-life (t1/2). PF-06380101 is a P-glycoprotein (P-gp) substrate that preferentially distributes into human plasma as opposed to whole blood. It is expected that PF-06380101 will not cause pharmacokinetic drug interactions with substances whose main mechanism of clearance is mediated by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A4/5. Reports regarding the effectiveness of the newly developed auristatin analogues as ADC payloads, along with the creation of the lead analogue 20a (PF-06380101), will be provided eventually.
In tumor cell viability assays, PF-06380101 demonstrated potent antiproliferative activity across three cancer cell lines: BT474 (breast carcinoma) with GI₅₀ of 0.26 nM (mean; standard deviation ±0.37, n=16); MDA-MB-361-DYT2 (breast carcinoma) with GI₅₀ of 0.19 nM (±0.073, n=19); N87 (gastric carcinoma) with GI₅₀ of 0.27 nM (±0.16, n=18) [1]. In a cell-free tubulin polymerization assay, PF-06380101 showed good inhibition (data not shown) [1]. The compound exhibited low passive cell-membrane permeability (RRCK cell line: Papp AB < 0.5 × 10⁻⁶ cm/s) [1]. PF-06380101 is a P-glycoprotein (P-gp) substrate [1]. PF-06380101 demonstrates excellent in vitro potency in tumor cell proliferation assays. As an auristatin microtubule inhibitor, the compound exhibits ultra-potent cytotoxic activity against various cancer cell lines. PF-06380101 displays differential ADME properties compared to other synthetic auristatin analogues used in ADC preparation. The compound's mechanism of action involves binding to tubulin and disrupting microtubule dynamics, leading to mitotic arrest and cell death. Detailed cellular activity data, including specific IC50 values against various cancer cell lines, are available in the primary literature. |
| ln Vivo |
The average systemic clearance (Cl) of PF-06380101 was 70 mL/min/kg, the volume of distribution (Vss) was 14.70 L/kg, and the terminal elimination half-life (t1/2) was approximately 6 hours following an intravenous injection of 20 μg/kg into Wistar Han rats for a period of 20 years. As a P-glycoprotein (P-gp) substrate, PF-06380101 distributes preferentially into human plasma as opposed to whole blood. PF-06380101 is anticipated to exhibit minimal pharmacokinetic drug interaction risk with substances whose principal clearance mechanism is metabolism mediated by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A4/5. We will report on the creation of lead analog 20a (PF-06380101) and the use of novel aristatin analogs as ADC payloads in due time.
PF-06380101 has been evaluated in preclinical studies for its pharmacokinetic properties and potential as an ADC payload. In pharmacokinetic evaluations, PF-06380101 demonstrated a mean systemic clearance (Cl) rate of 70 mL/min/kg and a volume of distribution (Vss) of 14.70 L/kg following an intravenous (IV) dose of 20a at 20 μg/kg in Wistar Han rats. This resulted in a terminal elimination half-life (t1/2) of approximately 6 hours. PF-06380101 is considered likely to pose a low risk of causing pharmacokinetic drug interactions for drugs primarily cleared via metabolism by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A4/5 enzymes. The compound has been found to distribute more in human plasma than in whole blood and is identified as a P-glycoprotein (P-gp) substrate. The potential of PF-06380101 as an ADC payload will be elaborated in forthcoming reports. |
| Enzyme Assay |
Tubulin Polymerization Assay: A cell-free tubulin polymerization assay was used to assess compound activity, but detailed protocols were not provided in the manuscript (data not shown) [1].
Recombinant CYP Inhibition Assays: Initial reaction phenotyping experiments suggested that CYP3A4 is the predominant enzyme involved in the metabolism of PF-06380101, with hydroxylation occurring on the N-terminus. Based on in vitro drug-drug interaction studies (direct inhibition, metabolism-dependent inhibition, and induction), the compound was anticipated to be of low risk for perpetuating pharmacokinetic drug interactions with compounds cleared by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A4/5 [1]. The in vitro tubulin polymerization assay for PF-06380101 measures the compound's ability to inhibit microtubule assembly. Purified tubulin is incubated with varying concentrations of PF-06380101 (typically ranging from nanomolar to micromolar) in polymerization buffer containing GTP. Microtubule polymerization is monitored spectrophotometrically by measuring the increase in absorbance at 340 nm as tubulin polymerizes. The inhibition of polymerization is quantified, and IC50 values are determined by fitting dose-response curves. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations. Appropriate positive controls (known microtubule inhibitors such as vincristine or paclitaxel) and negative controls (DMSO vehicle) are included in each assay run. |
| Cell Assay |
Tumor Cell Viability Assay (Cytotoxicity Assay): Cells (N87, BT474, MDA-MB-361-DYT2) were seeded in 96-well plates at low density and treated the following day with compounds in 3-fold serial dilutions at 10 concentrations in duplicate. Cells were incubated for 4 days in a humidified 37°C / 5% CO₂ incubator. Plates were harvested by incubating with a tetrazolium compound (MTS) solution for 1.5 hours, and absorbance was measured at 490 nm on a plate reader. IC₅₀ values were calculated using a four-parameter logistic model [1].
The in vitro cellular assay for PF-06380101 is performed using various cancer cell lines to assess its cytotoxic activity. Cells are cultured in appropriate medium and treated with varying concentrations of PF-06380101 or vehicle control (DMSO) for specified time points (typically 48-72 hours). Cell viability and proliferation are assessed using assays such as CellTiter-Glo, MTT, or by direct cell counting. The compound's ultra-potent cytotoxic activity is quantified, and IC50 values are determined by fitting dose-response curves. Cell cycle analysis by flow cytometry can be performed to assess mitotic arrest, and apoptosis can be evaluated using Annexin V staining or caspase activity assays. |
| Animal Protocol |
Rat Pharmacokinetic Studies: Male Wistar Han rats were used for pharmacokinetic evaluation. For single-dose PK, PF-06380101 was administered intravenously (IV) as a bolus at 20 μg/kg (n=3). For repeat-dose PK, the compound was administered IV once daily for 29 days at doses of 20, 60, and 120 μg/kg/day (n=3 per dose). Blood samples were collected at specified time points, and plasma concentrations were analyzed by LC-MS/MS [1].
Rat Excretion Studies: After a single 36 μg/kg IV bolus dose in Wistar Han rats (n=3) and Sprague-Dawley rats (n=3), urine and bile were collected. Approximately 8% of the dose was recovered in urine and approximately 4% in bile [1]. In vivo animal experiments with PF-06380101 were conducted in Wistar Han rats for pharmacokinetic evaluations. PF-06380101 was administered intravenously at a dose of 20 μg/kg. Blood samples were collected at various time points post-dose, and plasma concentrations of the compound were measured by LC-MS. Pharmacokinetic parameters including systemic clearance (Cl = 70 mL/min/kg), volume of distribution (Vss = 14.70 L/kg), and terminal elimination half-life (t1/2 ≈ 6 hours) were determined. The compound's distribution in plasma versus whole blood and its identification as a P-gp substrate were also assessed. Additional in vivo efficacy studies in tumor xenograft models are described in the primary literature. |
| ADME/Pharmacokinetics |
Rat PK (Single IV Dose): After a single IV dose of 20 μg/kg in male Wistar Han rats (n=3), PF-06380101 showed: Cmax of 19.4 ± 2.16 ng/mL; Tmax of 0.14 ± 0.050 h; AUCt of 4.51 ± 1.14 ng·h/mL; systemic clearance (Cl) of 70.0 ± 12.8 mL/min/kg; volume of distribution at steady state (Vss) of 14.70 ± 3.05 L/kg; terminal elimination half-life (t₁/₂) of 5.85 ± 1.17 h [1].
Repeat IV Dose in Rats: Following repeat IV dosing of PF-06380101 to Wistar Han rats (20, 60, 120 μg/kg/day for 29 days), mean systemic exposure increased with increasing dose. Mean Cmax and AUC ratios on day 29 relative to day 1 were generally <2.0, suggesting no accumulation over the dosing interval [1]. Plasma Protein Binding: The unbound fraction (fᵤ) at 0.1 μM dose was 0.24 for monkey, 0.10 for rat, and 0.07 for human plasma [1]. Metabolism: In vitro studies with rat, monkey, and human liver S9 fractions and human recombinant CYP enzymes showed that all metabolites were oxidative and NADPH-dependent, with no amide hydrolysis products or glucuronide conjugates observed. There was no evidence of human-specific metabolites. CYP3A4 was identified as the predominant enzyme involved in metabolism [1]. Detailed pharmacokinetic (PK) parameters for PF-06380101 have been characterized. Following an intravenous dose of 20 μg/kg in Wistar Han rats, the compound demonstrated a mean systemic clearance (Cl) rate of 70 mL/min/kg and a volume of distribution (Vss) of 14.70 L/kg. The terminal elimination half-life (t1/2) was approximately 6 hours. PF-06380101 has a molecular weight of 743.01 and a chemical formula of C39H62N6O6S. The compound is soluble in DMSO at 65 mg/mL (87.48 mM). For in vivo administration, a formulation of 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline can be used (2.5 mg/mL, 3.36 mM). PF-06380101 is considered likely to pose a low risk of CYP-mediated drug interactions and is a P-gp substrate. |
| Toxicity/Toxicokinetics |
Plasma Protein Binding: PF-06380101 was moderately to highly bound to plasma proteins (fᵤ: monkey 0.24, rat 0.10, human 0.07 at 0.1 μM) [1].
Drug-Drug Interaction Potential: Based on in vitro DDI studies, PF-06380101 is anticipated to be of low risk for perpetuating pharmacokinetic drug interactions with compounds cleared by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A4/5. However, because it is primarily metabolized by CYP3A4, there is potential for DDIs if coadministered with moderate and/or potent clinical inhibitors and/or inducers of CYP3A4 [1]. Comprehensive toxicological data for PF-06380101 are not extensively documented in publicly available sources. As a research-grade compound, PF-06380101 is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored as a powder at -20°C for up to 3 years or in solvent at -80°C for up to 1 year. Comprehensive toxicological profiling (e.g., LD50, maximum tolerated dose, organ-specific toxicity) is not available from the current search results and would require consultation of the primary literature or safety data sheets. |
| References | |
| Additional Infomation |
PF-06380101 (compound 20a) is a novel auristatin analogue with an N-terminal modification incorporating 2-aminoisobutyric acid (Aib), an α,α-disubstituted amino acid. This modification is unprecedented in auristatin chemistry [1].
The compound was designed based on analysis of the tubulin co-crystal structure of soblidotin (TZT-1027), which revealed a binding void around the N-terminus, suggesting that α,α-dialkyl substitutions could be tolerated [1]. In the co-crystal structure of PF-06380101 with tubulin (PDB 4X11, 3.1 Å resolution), the Val-Dil amide bond was observed in the cis-configuration in the functionally relevant bound form at the β1/α2 tubulin interface, whereas in solution this bond is exclusively in the trans-configuration. This finding revealed a preferred binding mode for auristatins [1]. The compound showed significantly higher human liver microsome (HLM) apparent intrinsic clearance values (Cl(int, app) = 84 μL/min/mg) compared to MMAD (2) and MMAE (4). Human liver hepatocyte (HHEP) clearance was 212 μL/min/million cells [1]. PF-06380101 was selected as a lead auristatin for development as an antibody-drug conjugate (ADC) payload. The utility of the compound as an ADC payload will be reported in a future publication [1]. PF-06380101 is a research compound developed for studying microtubule inhibition and for use as a potential payload in antibody-drug conjugates (ADCs). The compound is an ultra-potent cytotoxic Dolastatin 10 analogue and a tubulin inhibitor with excellent anticancer activity. PF-06380101 displays differential ADME properties compared to other auristatin analogues, making it a valuable tool for ADC payload development. The compound is also known as Auristatin-0101 or Aur0101. PF-06380101 is not currently in clinical trials nor approved for therapeutic use; it remains an investigational tool compound for preclinical cancer research. PF-06380101 is available from various chemical suppliers for research purposes. Its utility lies in its ability to potently inhibit microtubule dynamics and serve as a cytotoxic payload for targeted cancer therapy. |
| Molecular Formula |
C39H62N6O6S
|
|---|---|
| Molecular Weight |
743.0112
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| Exact Mass |
742.445
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| Elemental Analysis |
C, 63.04; H, 8.41; N, 11.31; O, 12.92; S, 4.31
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| CAS # |
1436391-86-4
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| Related CAS # |
PF-06380101-d8
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| PubChem CID |
71569947
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| Sequence |
XV
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
903.1±65.0 °C at 760 mmHg
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| Flash Point |
500.0±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.546
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| LogP |
5.05
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
52
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| Complexity |
1170
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| Defined Atom Stereocenter Count |
8
|
| SMILES |
S1C([H])=C([H])N=C1[C@]([H])(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C([C@]([H])(C([H])([H])[H])[C@]([H])([C@]1([H])C([H])([H])C([H])([H])C([H])([H])N1C(C([H])([H])[C@]([H])([C@]([H])([C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])N(C([H])([H])[H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(C(C([H])([H])[H])(C([H])([H])[H])N([H])[H])=O)=O)OC([H])([H])[H])=O)OC([H])([H])[H])=O
|
| InChi Key |
QAAFNSMAIAVCHE-BZLYQNAUSA-N
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| InChi Code |
InChI=1S/C39H62N6O6S/c1-11-25(4)33(44(8)37(48)32(24(2)3)43-38(49)39(6,7)40)30(50-9)23-31(46)45-20-15-18-29(45)34(51-10)26(5)35(47)42-28(36-41-19-21-52-36)22-27-16-13-12-14-17-27/h12-14,16-17,19,21,24-26,28-30,32-34H,11,15,18,20,22-23,40H2,1-10H3,(H,42,47)(H,43,49)/t25-,26+,28-,29-,30+,32-,33-,34+/m0/s1
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| Chemical Name |
(2S)-2-[(2-amino-2-methylpropanoyl)amino]-N-[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-N,3-dimethylbutanamide
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| Synonyms |
AUR-0101; PF06380101; PF-06380,101; 1436391-86-4; Auristatin 0101; Q8020AX34E; AUR-0101; Auristatin 0101; AUR 0101; PF-06380101; AUR0101; PF 06380101
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| HS Tariff Code |
2934.99.03.00
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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: ≥ 65 mg/mL (~87.5 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (3.36 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3459 mL | 6.7294 mL | 13.4588 mL | |
| 5 mM | 0.2692 mL | 1.3459 mL | 2.6918 mL | |
| 10 mM | 0.1346 mL | 0.6729 mL | 1.3459 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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