HSP70 inhibitors and methods of using same
AssigneesThe Wistar Institute, The Trustees of the University of Pennsylvania
InventorsMaureen E. Murphy, Joseph Salvino, Donna L. George, Julia Leu
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Abstract
The disclosure provides in one aspect compounds, and compositions comprising such compounds, that can be used to treat, ameliorate, and/or prevent cancer, especially colorectal cancer (CRC). In certain embodiments, the compounds of the disclosure inhibit HSP70. In other embodiments, the compounds of the disclosure promote or increase immune cell recruitment to a cancer. In yet other embodiments, the compounds of the disclosure promote and/or increase immune cell infiltration in a cancer.
Claims23
A compound of formula (I), or a salt, solvate, enantiomer, or tautomer thereof:
- BINDER-X—(Z1)m1—Y—(Z2)m2-L (I),
- wherein:
- BINDER is selected from the group consisting of:
- wherein:
- R2 and R3 are each independently R1, or
- R2 and R3 combine to form —O—, —S—, —NH—, or —N(C1-C6 alkyl)-;
- W1 is C(R1) or N;
- W2 is C(R1) or N;
- each occurrence of R1 is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, —N(R′)(R′), —C(═O)OR′, and —C(═O)NR′R′,
- wherein each occurrence of R′ is independently H or C1-C6 alkyl;
- n1 is selected from the group consisting of 0, 1, 2, 3, and 4;
- n2 is selected from the group consisting of 0, 1, 2, 3, 4, and 5;
- X is selected from the group consisting of —(CH2)1-5, —(CH2CH2O)1-5, —(OCH2CH2)1-5, —NHS(═O)2—*, —S(═O)2NH—*, —OC(═O)NH—*, and —NHC(═O)O—*,
- wherein the bond marked with * is formed with Z1;
- Y is selected from the group consisting of a chemical bond, *—OC(═O)—, and *—C(═O)O—,
- wherein the bond marked with * is formed with Z1;
- each occurrence of Z1 is independently selected from the group consisting of bond, —CH2—, —OCH2CH2—, and —CH2CH2O—;
- each occurrence of Z2 is independently selected from the group consisting of bond, —CH2—, —OCH2CH2—, and —CH2CH2O—;
- m1 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
- m2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
- with the proviso that X—(Z1)m1—Y—(Z2)m2-L does not comprise a O—O bond;
- L is a group selected from the group consisting of:
- wherein:
- each occurrence of Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, —N(R″)(R″), —C(═O)OR″, and —C(═O)NR″R″,
- wherein each occurrence of R″ is independently H or C1-C6 alkyl;
- Ri and Rj are independently H or optionally substituted C1-C6 alkyl;
- each occurrence of n, r1, r2, r3, r6, and r7 is independently selected from the group consisting of 1, 2, 3, 4, and 5;
- each occurrence of r4 is selected from the group consisting of 1, 2, and 3;
- and
- each occurrence of r5 is selected from the group consisting of 1, 2, 3, and 4.
A compound selected from the group consisting of:
- or a salt, solvate, enantiomer, or tautomer thereof.
Dependencies are inferred from the claim text.