OSW-1 analogs and conjugates, and uses thereof
AssigneePresident and Fellows of Harvard College
InventorsMatthew D. Shair, Anthony William George Burgett
Life of this patent
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Abstract
Provided are a number of compounds structurally related to OSW-1, a natural compound that binds OSBPs. Also provided are pharmaceutical compositions comprising the OSW-1 analogs, as well as methods for use of these OSW-1 analogs, or pharmaceutically acceptable salts, enantiomers, or stereoisomers thereof in the treatment of atherosclerosis. Alzheimer's disease, and cancer, including p21-deficient cancer. Conjugates of OSW-1 analogs with monoclonal antibodies, including monoclonal antibodies targeted to cancer cells, are also provided. Also provided are pharmaceutical compositions comprising the conjugates, as well as methods for use of these conjugates, in the treatment of cancer, including p21-deficient cancer.
Claims59
A conjugate comprising an antibody, or antigen-binding fragment thereof, covalently linked to a compound of formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R1, R2, R3, and R6 are independently selected from the group consisting of hydrogen, trialkylsilyl, and
- Z is absent or is selected from the group consisting of O and NR10;
- n is an integer 0-6;
- R is selected from the group consisting of substituted or unsubstituted:
- alkyl, alkenyl, amino, alloc-protected amino, Fmoc-protected amino, aryl, 5- to 13-membered cycloalkyl or cycloalkenyl group, and 5- to 10-membered cyclic heteroaromatic group comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
- R4 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- R5 is selected from the group consisting of hydrogen and acyl;
- and
- R10 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- provided that at least one of R1, R2, R3, R4, R5, and R6 is not hydrogen.
A compound selected from the group consisting of:
- and pharmaceutically acceptable salts thereof.
A compound of formula (II):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- X is selected from the group consisting of O and NOR20;
- R1, R2, and R3 are independently selected from the group consisting of hydrogen, R20, trialkylsilyl, and
- Z is absent or is selected from the group consisting of O and NR10;
- n is an integer 0-6;
- R is selected from the group consisting of substituted or unsubstituted:
- alkyl, alkenyl, amino, alloc-protected amino, Fmoc-protected amino, aryl, 5- to 13-membered cycloalkyl or cycloalkenyl group, and 5- to 10-membered cyclic heteroaromatic group comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
- R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, and R20;
- R10 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- R20 is selected from the group consisting of
- Z′ is selected from the group consisting of O and NR10;
- and
- m is an integer 1-6;
- provided that if X is O, then one and only one of R1, R2, R3, and R4 is R20;
- and if X is NOR20, then none of R1, R2, R3, and R4 is R20.
A compound of formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R1, R2, and R3 are independently selected from the group consisting of hydrogen, trialkylsilyl, and
- provided at least one instance of R1, R2, or R3 is
- wherein Z is O;
- R6 is
- Z is absent or is selected from the group consisting of O and NR10;
- n is an integer 0-6;
- R is selected from the group consisting of substituted or unsubstituted:
- alkyl, alkenyl, amino, alloc-protected amino, Fmoc-protected amino, aryl, 5- to 13-membered cycloalkyl or cycloalkenyl group, and 5- to 10-membered cyclic heteroaromatic group comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
- R4 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- R5 is acyl;
- and
- R10 is selected from the group consisting of hydrogen and C1-C6 alkyl.
A compound of formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R1, R2, and R3 are independently selected from the group consisting of hydrogen, trialkylsilyl, and
- provided that R2 and R3 not hydrogen, or R1 and R3 are not hydrogen, or R1 and R2 are not hydrogen;
- R6 is
- Z is absent or is selected from the group consisting of O and NR10;
- n is an integer 0-6;
- R is selected from the group consisting of substituted or unsubstituted:
- alkyl, alkenyl, amino, alloc-protected amino, Fmoc-protected amino, aryl, 5- to 13-membered cycloalkyl or cycloalkenyl group, and 5- to 10-membered cyclic heteroaromatic group comprising 1-3 heteroatoms independently selected from the group consisting of N, O, and S;
- R4 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- R5 is acyl;
- and
- R10 is selected from the group consisting of hydrogen and C1-C6 alkyl.
Dependencies are inferred from the claim text.