Silvestrol antibody-drug conjugates and methods of use
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.
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.