PF-06380101

Alias: AUR-0101; PF06380101; Auristatin 0101; AUR 0101; PF-06380101; AUR0101; PF 06380101
Cat No.:V4474 Purity: ≥98%
PF-06380101 (Auristatin 0101; PF06380101; AUR-0101) is a novel and ultra-potent cytotoxic Dolastatin 10 analogue and a tubulin inhibitor with excellent anticancer activity.
PF-06380101 Chemical Structure CAS No.: 1436391-86-4
Product category: Microtubule(Tubulin)
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

PF-06380101 (Auristatin 0101; PF06380101; AUR-0101) is a novel and ultra-potent cytotoxic Dolastatin 10 analogue and a tubulin inhibitor with excellent anticancer activity. It exhibits differential ADME properties and high potencies in tumor cell proliferation assays when compared to other synthetic auristatin analogues used in ADC preparation. Clinically employed as payloads in antibody-drug conjugates (ADCs), auristatins are synthetic analogues of the naturally occurring antitumor compound Dolastatin 10. They are extremely potent cytotoxic microtubule inhibitors. Our lead auristatin, PF-06380101, is discovered and the design and synthesis of several new auristatin analogues with N-terminal modifications, including amino acids with α,α-disubstituted carbon atoms, are described. Comparing these novel peptide structure modifications to other synthetic auristatin analogues used in the creation of ADCs, the results were analogues with superior potencies in tumor cell proliferation assays and distinct ADME characteristics. Furthermore, tubulin and auristatin cocrystal structures that enable a thorough analysis of their binding mechanisms are presented. Surprisingly, in their functionally relevant tubulin bound state, all the analyzed analogues have a cis-configuration at the Val-Dil amide bond, whereas in solution this bond is exclusively in the trans-configuration. This astounding finding provides insight into the preferred binding mode of auristatins and is a useful resource for structure-based drug design.

Biological Activity I Assay Protocols (From Reference)
Targets
Auristatin
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.
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.
References
[1]. Maderna A, et al. Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications. J Med Chem. 2014 Dec 26;57(24):10527-43.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C39H62N6O6S
Molecular Weight
743.0112
Exact Mass
742.45
Elemental Analysis
C, 63.04; H, 8.41; N, 11.31; O, 12.92; S, 4.31
CAS #
1436391-86-4
Appearance
Solid powder
SMILES
CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@@H](CC2=CC=CC=C2)C3=NC=CS3)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)C(C)(C)N
InChi Key
QAAFNSMAIAVCHE-BZLYQNAUSA-N
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
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
Synonyms
AUR-0101; PF06380101; Auristatin 0101; AUR 0101; PF-06380101; AUR0101; PF 06380101
HS Tariff Code
2934.99.03.00
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)
Solubility Data
Solubility (In Vitro)
DMSO: ≥ 65 mg/mL (~87.5 mM)
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.

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