Methods of using monomethylvaline compositions having phenylalanine carboxy modifications at the C-terminus

US9522194B2 · kind B2 · utility

Assignee

• SEATTLE GENETICS, INC. · US

Inventors

• Svetlana O. Doronina · Snohomish, US
• Toni Kline · Seattle, US
• Scott Jeffrey · Bothell, US
• Peter D. Senter · Seattle, US
• Damon Meyer · Bellevue, US

Key dates

• Filing date: Sep 30, 2014
• Grant date: Dec 20, 2016
• Expiry date: Sep 30, 2034

Classification

• Technology area (CPC Y): Emerging Cross-Sectional Technologies
• CPC primary: Y02A50/30
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine were prepared and attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand-drug conjugates were active in vitro and in vivo in inhibiting cell proliferation and are represented by the general structure ofLv-[(LU)0-1-(D)1-4]p wherein L- is Ligand unit; LU is a Linker unit (LU); v is 1; p is an number ranging from about 1 to about 20; and D is a drug moiety having the formula:wherein the moiety —N(R9)Z1 is a phenylalanine bioisostere, wherein Z1 is —CH(R10)Z2 so that the phenylalanine bioisostere has the structure of Formula A:and wherein the substituents R2-R10, X1 and Z2 are as defined.