Silvestrol antibody-drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-10639378-B2
Application number	US-201715613477-A
Country	US
Kind code	B2
Filing date	Jun 5, 2017
Priority date	Jun 6, 2016
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

The invention relates generally to a silvestrol molecule activated with a leaving group. The invention further relates generally to an antibody-drug conjugate comprising an antibody conjugated by a linker to one or more silvestrol drug moieties and methods of treatment.

First claim

What is claimed is:

1. A silvestrol-linker intermediate compound of Formula II:

or a salt thereof;
wherein
R a is a group selected from CH 3 O, CN, NO 2 , and Cl;
R 1 is selected from —OCH 3 and L-X;
R 2 is selected from —CH(OH)CH 2 OH, and L-X;
where one of R 1 and R 2 is L-X;
L is a linker selected from the formulas:
-Str-PM-Y—

and
-Str-Pep-Y—

where Str is a stretcher unit covalently attached to X; PM is a peptidomimetic unit, Pep is a peptide of two to twelve amino acid residues, and Y is a spacer unit selected from para-aminobenzyl and para-aminobenzyloxycarbonyl, covalently attached to the silvestrol drug moiety, or
L is selected from —CH 2 CH 2 —, —CH 2 CH 2 NH—, —CH 2 CH 2 NHC(O)OCH 2 CH(OH)—, —CH 2 CH 2 OCH 2 CH(OH)—; and
X is selected from:

where the wavy lines indicate the attachments to L;
R 3 is NO 2 , Cl, F, CN or Br, and a is 0, 1, or 2.

2. The silvestrol-linker intermediate compound of claim 1 wherein L is a protease-cleavable, non-peptide linker having the formula:
-Str-PM-Y—

3. The silvestrol-linker intermediate compound of claim 2 wherein Str is (CH 2 ) 5 .

4. The silvestrol-linker intermediate compound of claim 2 wherein PM has the formula:

where R 7 and R 8 together form a C 3 -C 7 cycloalkyl ring, and
AA is an amino acid side chain selected from H, —CH 3 , —CH 2 (C 6 H 5 ), —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , —CHCH(CH 3 )CH 3 , and —CH 2 CH 2 CH 2 NHC(O)NH 2 .

5. The silvestrol-linker intermediate compound of claim 4 wherein R 7 and R 8 together form cyclobutyl.

6. A silvestrol-linker intermediate compound selected from:

or a salt thereof.

7. The silvestrol-linker intermediate compound of claim 6 having the structure:

or a salt thereof.

Assignees

• Genentech Inc

Inventors

• Pillow Thomas
• Polson Andrew G
• Zheng Bing

Classifications

• A61K2039/627

  characterised by the linker · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title