Inhibitors for steroid response elements and rna polymerase ii and related methods
AssigneeCalifornia Institute of Technology
InventorsPeter B. Dervan, Nicholas G. Nickols, Fei Yang
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Abstract
The present invention relates to polyamides capable of inhibiting ARE-, GRE- and ERE-mediated gene regulation in cells. The present invention also relates to polyamides capable of modulating the activity of RNA polymerase II and p53. The invention also relates to methods to treat diseases related to ARE-, GRE- and ERE-mediated gene regulation and to RNA polymerase II and p53 activity.
Claims17
A composition to modulate steroid receptor-mediated gene expression in a cell comprising a polyamide of structure 1;
- wherein each X is independently selected from CH, N, or COH;
- and wherein each pyrrole unit of structure 2 may be independently replaced by a beta-alanine of structure 3;
- and wherein each R2 is independently selected from H, a C1-10 alkyl, a C1-10 alkenyl, a C1-10 alkynyl, —(CH2)q—NH—R6, another R2;
- and wherein a R3 may be linked to a R4 and a R1 may be linked to a R5 through a turn of any one of structures 4-6;
- and wherein each R7, R8 and R9 is independently selected from structures 7-17;
- and wherein each R1, R4 and R10 are independently selected from structures 18, with each A independently selected from structure 21;
- and wherein each R3, R5, R6 and R11 are independently selected from structures 19 and 20, with each A′ independently selected from structures 22, and with each Z independently selected from structures 23 and 24;
- and wherein each R12 is independently selected from structures 25-54, with each y independently selected from structures 55-57;
- and wherein each R13 is independently selected from structures 58-74;
- and wherein each R14 represents one, two, three, four, or five sidechains up to the maximum number with each R14 being independently selected from H, OH, SH, CH3, NH2, halogen, F, Cl, Br, and I;
- and wherein in R12 and R13, each amide linkage of structure 75 may be independently replaced by a thiourea linkage of structure 76;
- and wherein each d, e, f, g, h, j, q is independently selected from 1-10, and each p, s, u, v, w is independently selected from 0 and 1;
- and wherein said steroid receptor is selected from the group consisting of AR, GR and ER.
A method of treating a disease comprising administering a composition to a patient, said composition comprising a polyamide of structure 1;
- wherein each X is independently selected from CH, N, or COH;
- and wherein each pyrrole unit of structure 2 may be independently replaced by a beta-alanine of structure 3;
- and wherein each R2 is independently selected from H, a C1-10 alkyl, a C1-10 alkenyl, a C1-10 alkynyl, —(CH2)q-NH—R6, another R2;
- and wherein a R3 may be linked to a R4 and a R1 may be linked to a R5 through a turn of any one of structures 4-6;
- and wherein each R7, R8 and R9 is independently selected from structures 7-17;
- and wherein each R1, R4 and R10 are independently selected from structures 18, with each A independently selected from structure 21;
- and wherein each R3, R5, R6 and R11 are independently selected from structures 19 and 20, with each A′ independently selected from structures 22, and with each Z independently selected from structures 23 and 24;
- and wherein each R12 is independently selected from structures 25-54, with each y independently selected from structures 55-57;
- and wherein each R13 is independently selected from structures 58-74;
- and wherein each R14 represents one, two, three, four, or five sidechains up to the maximum number with each R14 being independently selected from H, OH, SH, CH3, NH2, halogen, F, Cl, Br, and I;
- and wherein in R12 and R13, each amide linkage of structure 75 may be independently replaced by a thiourea linkage of structure 76;
- and wherein each d, e, f, g, h, j, q is independently selected from 1-10, and each p, s, u, v, w is independently selected from 0 and 1;
- and wherein said steroid receptor is selected from the group consisting of AR, GR and ER.
The method of claim 13, wherein said polyamide has at least 5-fold greater affinity for an ARE, a GRE, or an ERE than for a site differing from an ARE, a GRE, or an ERE by two base pairs.
The method of claim 13, wherein said composition is capable of changing the level of expression of a gene by at least two fold, wherein said gene is regulated by an ARE, a GRE, or an ERE.
The method of claim 13, wherein said disease is selected from the group consisting of cancer, prostate cancer, a prostate-specific disease, hair-loss, alopecia, male-pattern hair loss, breast cancer, an inflammatory disease, a diseases involving inflammation, a fertility disorder, ovarian cancer, colorectal cancer, endometrial cancer, osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, obesity and metabolic diseases.
A composition comprising a polyamide selected from the group consisting of structures 92 and 93;
- wherein R15 is selected from structures 94-97;
- wherein each m, n, o is independently selected from 1-10;
- wherein each R16-R23 is independently selected from structures 98-107;
- wherein each q is independently selected from 1-10;
- and wherein each X′ and Y′ are independently selected from H, OH, SH, CH3, CH2CH3, NH2, NO2, GOON, COOMe, COOEt, F, Cl, Br, and I.
A method of treating a disease comprising administering a composition to a patient, said composition comprising a polyamide selected from the group consisting of structures 92 and 93;
- wherein R15 is selected from structures 94-97;
- wherein each m, n, o is independently selected from 1-10;
- wherein each R16-R23 is independently selected from structures 98-107;
- wherein each q is independently selected from 1-10;
- and wherein each X′ and Y′ are independently selected from H, OH, SH, CH3, CH2CH3, NH2, NO2, COOH, COOMe, COOEt, F, Cl, Br, and I.
Dependencies are inferred from the claim text.