Inhibitors of hedgehog signaling pathways, compositions and uses related thereto
AssigneeJohn Hopkins University School of Medicine
InventorsPhilip Beachy, Michael Cooper, Jeffery Porter
Life of this patent
Estimating the term…
Abstract
The present invention makes availables assays and reagents inhibiting paracrine and/or autocrine signals produced by a hedgehog protein or aberrant activation of a hedgehog signal transduction pathway, e.g., which involve the use of a steroidal alkaloid or other small molecule.
Claims17
1-26. (canceled)
An in vitro method for inhibiting mitotic cell proliferation in a cell, comprising contacting the cell in vitro with a compound represented in the general formula (I), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:
- wherein, as valence permits,
- R2, R3, R4, and R5 independently for each occurrence, represent one or more substituents selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R6, R7, and R′7 are absent or represent, independently for each occurrence, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8, or
- R6 and R7, or R7 and R′7, taken together form a ring or polycyclic ring;
- 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
- m is an integer in the range 0 to 8 inclusive.
An in vitro method for inhibiting mitotic cell proliferation in a cell, comprising contacting the cell in vitro with a compound represented in the general formula (II), or unsaturated forms thereof, or pharmaceutically acceptable salts thereof:
- wherein, as valence permits,
- R2 and R4, independently for each occurrence, are selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R3, independently for each occurrence, is selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R5, independently for each occurrence, is absent or represents a substituent selected from hydrogen, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8;
- R6, R7, and R′7 are absent or represent, independently, halogens, alkyls, alkenyls, alkynyls, aryls, hydroxyl, ═O, ═S, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, carboxamides, anhydrides, silyls, ethers, thioethers, alkylsulfonyls, arylsulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH2)m—R8, or
- R6 and R7, or R′7 and R′7, taken together form a ring or polycyclic ring,
- 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;
- X represents O or S;
- and
- m is an integer in the range 0 to 8 inclusive.
Dependencies are inferred from the claim text.