PF-06380101

• CAT Number: I001686
• CAS Number: 1436391-86-4
• Molecular Formula: C39H62N6O6S
• Molecular Weight: 743.01
• Purity: ≥95%
• Target: ADCs cytotoxin; tubulin inhibitor
• Solubility: DMSO: ≥ 65 mg/mL
• Storage: Store at -20°C
• IC50: ~0.2 nM(GI50 in BT474, MDA-MB-361-DYT2 and N87 cell line) [1]
• IUPAC 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
• InChI: 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
• InChIKey: QAAFNSMAIAVCHE-BZLYQNAUSA-N
• SMILES: CCC(C)C(C(CC(=O)N1CCCC1C(C(C)C(=O)NC(CC2=CC=CC=C2)C3=NC=CS3)OC)OC)N(C)C(=O)C(C(C)C)NC(=O)C(C)(C)N

PF-06380101 (CAT: I001686) is a potent cytotoxic Dolastatin 10 analog with high efficacy against tumor cells. It exhibits favorable pharmacokinetic properties and differs from other auristatin analogs used in antibody-drug conjugates (ADCs). In preclinical studies, it demonstrated rapid clearance and moderate volume of distribution, resulting in a relatively short half-life of approximately 6 hours. PF-06380101 shows preferential distribution into human plasma and is a substrate of P-glycoprotein. Importantly, it is unlikely to cause significant drug interactions with compounds metabolized by specific liver enzymes.

Reference

1. J Med Chem. 2014 Dec 26;57(24):10527-43. doi: 10.1021/jm501649k. Epub 2014 Dec
9.

Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.

Maderna A(1), Doroski M, Subramanyam C, Porte A, Leverett CA, Vetelino BC, Chen
Z, Risley H, Parris K, Pandit J, Varghese AH, Shanker S, Song C, Sukuru SC,
Farley KA, Wagenaar MM, Shapiro MJ, Musto S, Lam MH, Loganzo F, O’Donnell CJ.

Author information:
(1)Worldwide Medicinal Chemistry, Oncology, Pfizer Worldwide Research and
Development , Eastern Point Road, Groton, Connecticut 06340, United States.

Auristatins, synthetic analogues of the antineoplastic natural product
Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are
clinically used as payloads in antibody-drug conjugates (ADCs). The design and
synthesis of several new auristatin analogues with N-terminal modifications that
include amino acids with α,α-disubstituted carbon atoms are described, including
the discovery of our lead auristatin, PF-06380101. This modification of the
peptide structure is unprecedented and led to analogues with excellent potencies
in tumor cell proliferation assays and differential ADME properties when
compared to other synthetic auristatin analogues that are used in the
preparation of ADCs. In addition, auristatin cocrystal structures with tubulin
are being presented that allow for the detailed examination of their binding
modes. A surprising finding is that all analyzed analogues have a
cis-configuration at the Val-Dil amide bond in their functionally relevant
tubulin bound state, whereas in solution this bond is exclusively in the
trans-configuration. This remarkable observation shines light onto the preferred
binding mode of auristatins and serves as a valuable tool for structure-based
drug design.