Small Molecule HSP70 Inhibitors

摘要

In an effort to discover therapies for treating HSP70 related diseases, a previously unidentified hydrophobic pocket was found in the C-terminal domain of DnaK and of human HSP70. A novel chemical scaffold was also discovered for identifying compounds that treat diseases related to this hydrophobic pocket. The compounds have the structure of the formula (I), wherein L, M, and R1-R5 are defined herein and are, therefore, in these therapies, optionally with other pharmaceutical agents such as genotoxic agents. Accordingly these compounds are useful in inhibiting HSP70 or DnaK, reducing HSP70 in mitochondria of a cancer cell, treating malignant neoplastic disease, or inhibiting or reducing bacterial growth. These compounds also resulted in novel methods of screening for a HSP70 inhibitor or DnaK inhibitor by using the three-dimensional structure of the hydrophobic pocket in DnaK or HSP70.;

主权项

1. A composition comprising
(a) a compound of formula (I) of the structure:wherein:
L is absent or a noncleavable organic moiety; M is a ligand which promotes one or more of cellular uptake, delivery, or penetration of a small molecule through one or more of a cell wall, cell membrane, plasma membrane, or subcellular membrane; and R1 to R5 are, independently, selected from the group consisting of H, optionally substituted C1 to C10 alkyl, optionally substituted C1 to C10 alkenyl, optionally substituted C1 to C10 alkynyl, OH, halogen, NH2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted C1 to C10 alkoxy, optionally substituted C1 to C10 hydroxyalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycleoxy, optionally substituted C1 to C10 alkylthio, optionally substituted C1 to C10 alkylsulfonyl, optionally substituted C1 to C10 alkylcarbonylamino, optionally substituted alkylsulfonylamino, optionally substituted C1 to C10 alkylamino, optionally substituted C1 to C10 dialkylamino, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted heterocycleamino, optionally substituted C1 to C10 amido, NO2, optionally substituted C1 to C10 carboxy, optionally substituted C1 to C10 alkoxycarbonyl, optionally substituted C1 to C10 alkylcarbonyl, optionally substituted C1 to C10 alkylcarbonyloxy, optionally substituted alkylaminocarbonyl, optionally substituted arylaminocarbonyl, optionally substituted heteroarylaminocarbonyl, optionally substituted heterocycleaminocarbonyl, phosphate, sulfamido and sulfonamide; or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof; with the proviso when (i) L is absent, (ii) M is PPh3 or PPh2CH3 and (iii) the compound is a bromide salt, not all of R1 to R5 are H; and (b) optionally one or more of
a pharmaceutically acceptable carrier or excipient; anda genotoxic agent or pharmaceutically acceptable salt, prodrug, solvate or metabolite thereof.