Claims
- 1. A method for inhibiting an altered growth state of a cell having a ptc loss-of-function phenotype or a smoothened gain-of-function phenotype, comprising contacting the cell with a ptc agonist in a sufficient amount to inhibit the altered growth state, wherein the ptc agonist is a organic molecule having a molecular weight less than about 750 amu.
- 2. A method for inhibiting aberrant proliferation of a cell having a ptc loss-of-function phenotype or a smoothened gain-of-function phenotype comprising contacting the cell with a ptc agonist in a sufficient amount to inhibit proliferation of the cell.
- 3. The method of claim 1, wherein the ptc agonist causes repression of smoothened-mediated signal transduction.
- 4. The method of claim 1, wherein the ptc agonist is a steroidal alkaloid.
- 5. The method of claim 4, wherein the steroidal alkaloid is represented in the general formulas (I), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 6. The method of claim 5, wherein:
R2 and R3, for each occurrence, is an —OH, alkyl, —O-alkyl, —C(O)-alkyl, or —C(O)-R8; R4, for each occurrence, is an absent, or represents —OH, ═O, alkyl, —O-alkyl, —C(O)-alkyl, or —C(O)—R8; R6, R7, and R′7 each independently represent, hydrogen, alkyls, alkenyls, alkynyls, amines, imines, amides, carbonyls, carboxyls, carboxamides, ethers, thioethers, esters, or —(CH2)m—R8, or R7, and R′7 taken together form a furanopiperidine, such as perhydrofuro[3,2-b]pyridine, a pyranopiperidine, a quinoline, an indole, a pyranopyrrole, a naphthyridine, a thiofuranopiperidine, or a thiopyranopiperidine with the proviso that at least one of R6, R7, or R′7 is present and includes a primary or secondary amine; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle, and preferably R8 is a piperidine, pyrimidine, morpholine, thiomorpholine, pyridazine,
- 7. The method of claim 4, wherein the steroidal alkaloid is represented in the general formula (II), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 8. The method of claim 4, wherein the steroidal alkaloid is represented in the general formula (III), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 9. The method of claim 4, wherein the steroidal alkaloid is represented in the general formula (IV), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 10. The method of claim 4, wherein the steroidal alkaloid is represented in the general formula (V) or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 11. The method of claim 4, wherein the steroidal alkaloid is represented in the general formula (VI), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 12. The method of claim 4, wherein the steroidal alkaloid is represented in the general formula (VII) or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 13. The method of claim 4, wherein the steroidal alkaloid does not substantially interfere with the biological activity of such steroids as aldosterone, androstane, androstene, androstenedione, androsterone, cholecalciferol, cholestane, cholic acid, corticosterone, cortisol, cortisol acetate, cortisone, cortisone acetate, deoxycorticosterone, digitoxigenin, ergocalciferol, ergosterol, estradiol- 17-α, estradiol-17-β, estriol, estrane, estrone, hydrocortisone, lanosterol, lithocholic acid, mestranol, β-methasone, prednisone, pregnane, pregnenolone, progesterone, spironolactone, testosterone, triamcinolone and their derivatives.
- 14. The method of claim 4, wherein the steroidal alkaloid does not specifically bind a nuclear hormone receptor.
- 15. The method of claim 4, wherein the steroidal alkaloid does not specifically bind estrogen or testerone receptors.
- 16. The method of claim 4, wherein the steroidal alkaloid has no estrogenic activity at therapeutic concentrations.
- 17. The method of claim 1, wherein the ptc agonist inhibits ptc loss-of-function or smoothened gain-of-function mediated signal transduction with an ED50 of 1 mM or less.
- 18. The method of claim 1, wherein the ptc agonist inhibits ptc loss-of-function or smoothened gain-of-function mediated signal transduction with an ED50 Of 1 μM or less.
- 19. The method of claim 1, wherein the ptc agonist inhibits ptc loss-of-function or smoothened gain-of-function mediated signal transduction with an ED50 of 1 nM or less.
- 20. The method of claim 1, wherein the cell is contacted with the ptc agonist in vitro.
- 21. The method of claim 1, wherein the cell is contacted with the ptc agonist in vivo.
- 22. The method of claim 1, wherein the ptc agonist is administered as part of a therapeutic or cosmetic application.
- 23. The method of claim 22, wherein the therapeutic or cosmetic application is selected from the group consisting of regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primative gut, regulation of hematopoietic function, regulation of skin and hair growth, etc.
- 24. A pharmaceutical preparation comprising a steroidal alkaloid represented in the general formulas (I), or unsaturated forms thereof and/or seco-, nor- or homo-derivatives thereof:
- 25. A method for inhibiting an altered growth state of a cell having a ptc loss-of-function phenotype, hedgehog gain-of-function phenotype, or a smoothened gain-of-function phenotype, comprising contacting the cell with a composition including at least one cAMP agonist.
- 26. The method of claim 25, wherein at least one cAMP agonist activates adenylate cyclase.
- 27. The method of claim 25, wherein at least one cAMP agonist is a cAMP analog.
- 28. The method of claim 25, wherein at least one cAMP agonist is a cAMP phosphodiesterase inhibitor.
- 29. The method of claim 25, wherein the composition inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED50 of 1 mM or less.
- 30. The method of claim 25, wherein the composition inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED50 of 1 μM or less.
- 31. The method of claim 25, wherein the composition inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED50 of 1 nM or less.
- 32. The method of claim 25, wherein the cell is contacted with the composition in vitro.
- 33. The method of claim 25, wherein the cell is contacted with the composition in vivo.
- 34. The method of claim 25, wherein the composition is administered as part of a therapeutic or cosmetic application.
- 35. The method of claim 34, wherein the therapeutic or cosmetic application is selected from the group consisting of regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primative gut, regulation of hematopoietic function, regulation of skin and hair growth, etc.
- 36. The method of claim 25, wherein the composition includes forskolin or a derivative thereof.
- 37. A method for treating or preventing basal cell carcinoma, comprising administering a composition including a cAMP agonist to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.
- 38. A method for inhibiting an altered growth state of a cell having a ptc loss-of-function phenotype, hedgehog gain-of-function phenotype, or a smoothened gain-of-function phenotype, comprising
determining the phenotype of the cell; and if the phenotype is a ptc loss-of-function, hedgehog gain-of-function, or a smoothened gain-of-function phenotype, treating the cell with a cAMP agonist in an amount sufficient to inhibit the altered growth state of the cell.
Parent Case Info
[0001] This application is based on U.S. Provisional Application Ser. No. 60/115,642, filed Jan. 13, 1999, U.S. Provisional Application No. 60/119,594, filed Feb. 10, 1999, and U.S. Provisional Application No. 60/142,124, filed Jul. 2, 1999, all hereby incorporated by reference in their entireties.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60115642 |
Jan 1999 |
US |
|
60119594 |
Feb 1999 |
US |
|
60142124 |
Jul 1999 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09417564 |
Oct 1999 |
US |
Child |
09867311 |
May 2001 |
US |