Mediators of hedgehog signaling pathways, compositions and uses related thereto
AssigneeCurtis, Inc.
InventorsAnthony David Baxter, Edward Andrew Boyd, Oivin M. Guicherit, Stephen Price, Lee D. Rubin
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Abstract
The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function by contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize hedgehog activity.
Claims35
A method for inhibiting signaling via a hedgehog pathway in a cell comprising contacting the cell with a hedgehog antagonist, wherein the hedgehog antagonist is an organic molecule represented in the general formula (II):
- wherein, as valence permits,
- R1 and R2, independently for each occurrence, represent H, lower alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);
- L, independently for each occurrence, is absent or represents —(CH2)n-alkyl, —(CH2)nO(CH2)p—, —(CH2)nNR2(CH2)p—, —(CH2)nS(CH2)p—, —(CH2)nalkenyl(CH2)p—, —(CH2)nalkynyl(CH2)p—, —O(CH2)n—, —NR2(CH2)n—, or —S(CH2)n—;
- X is selected from —N(R8)—, —O—, —S—, —Se—, —N═N—, —ON═CH—, —(R8)N—N(R8)—, —ON(R8)—, a heterocycle, or a direct bond between L and Y;
- Y is selected from —C(═O)—, —C(═S)—, —S(O2)—, —S(O)—, —C(═NCN)—, —P(═O)(OR2)—, a heteroaromatic group, or a direct bond between X and Z;
- Z is selected from —N(R8)—, —O—, —S—, —Se—, —N═N—, —ON═CH—, —R8N—NR8—, —ONR8—, a heterocycle, or a direct bond between Y and L;
- R8, independently for each occurrence, represents H, lower alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted), or two R8 taken together form a 4- to 8-membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;
- W represents a substituted or unsubsituted aryl or heteroaryl ring fused to the pyrimidone ring;
- p represents, independently for each occurrence, an integer from 0 to 10;
- and
- n, individually for each occurrence, represents an integer from 0 to 10.
The method of claim 23, wherein W represents a substituted or unsubstituted heteroaryl ring fused to the pyrimidone ring.
Dependencies are inferred from the claim text.