Radiotherapeutic and companion imaging agents to target mc1r

Abstract

The subject matter disclosed herein relates generally to cancer therapy and to anti-cancer compounds and imaging agents. More specifically, the subject matter disclosed herein relates to agents that target MC1R and their use in the treatment of cancer. Methods of screening for MC1R targeted agents are also disclosed.

1 . A compound having Formula I. 
       
         
           
           
               
               
           
         
         wherein 
         P 1  and P 2  are independently H, amine protecting groups, or one or more additional amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, proline, histidine, methionine, methionine sulfoxide, phenylalanine, serine, threonine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, O-methylserine, O-ethylserine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine, NH 2 —CH(CH 2 CHEt 2 )-COOH, alpha-aminoheptanoic acid, NH 2 —CH(CH 2 -cyclohexyl)-COOH, NH 2 —CH(CH 2 -cyclopentyl)-COOH, NH 2 —CH(CH 2 -cyclobutyl)-COOH, NH 2 —CH(CH 2 -cyclopropyl)-COOH, 5,5,5-trifluoroleucine, α-aminohexanoic acid, thiaproline, and hexafluoroleucine; 
         L is an optional linking moiety of from 1 to 30 carbon atoms in length; 
         A 1  is a radionuclide chelating moiety, 
         or an ionized derivative thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein P 1  and P 2  are independently H or amine protecting groups selected from the group consisting of trityl, Fmoc, Boc, benzyl, acetate, 4-phenylbutyryl, and Ac-homophenylalanine. 
     
     
         3 . The compound of  claim 1 , wherein P 1  is 4-phenylbutyryl and P 2  is H. 
     
     
         4 . The compound of  claim 1 , wherein L is absent. 
     
     
         5 . The compound of  claim 1 , wherein L is R 14 , C(O)R 14 C(O), C(O)OR 14 OC(O), C(O)R 14 N, C(O)OR 14 NH, NHR 14 NH, or C(O)NHR 14 NHC(O), C(S)OR 14 OC(S); wherein R 14  is O, S, C 1 -C 20  alkyl; C 1 -C 20  heteroalkyl; C 1 -C 20  alkylamine; C 1 -C 20  alkoxyl; C 1 -C 20  alkanoyloxyl; or C 1 -C 20  alkylamido, any of which can be optionally substituted with one or more substituents including halogen, alkoxyl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, amine, cyano, nitro, hydroxyl, carbonyl, acyl, carboxylic acid (—COOH), —C(O)R 12 , —C(O)OR 12 , —COO—, —CONH 2 , —CONHR 12 , —C(O)NR 12 R 13 , —NR 12 R 13 , —NR 12 S(O) 2 R 13 , —NR 12 C(O)R 13 , —S(O) 2 R 12 , —SR 12 , and —S(O) 2 NR 12 R 13 , —SOR 12 ), and —SOOR 12 ;
 wherein R 12  and R 13  can each independently be hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl, cyano, amino, alkylamino, dialkylamino, alkoxyl, aryloxyl, cycloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl. 
 
     
     
         6 . The compound of  claim 1 , wherein L is C(O)NH(CH 2 ) n —, where n is from 1 to 20, or C(O)CH 2 O) n , where n is from 1 to 10. 
     
     
         7 . The compound of  claim 1 , wherein A 1  is DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid). 
     
     
         8 . The compound of  claim 1 , wherein A 1  is selected from the group consisting of DTPA (diethylene triamine pentaacetic acid), DOTP (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic) acid), DOTMA, (1R, 4R, 7R, 10R)-α′α″α′″-Tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) tetrasodium salt, TETA, (1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), DOTAM (1,4,7,10-Tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4, 11-dicetic acid), and NOTA ((1,4,7-triazacyclononane-N,N′,N″-triacetic acid). 
     
     
         9 . The compound of  claim 1 , wherein the compound has Formula IA 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound has a formula chosen from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , further comprising a radionuclide. 
     
     
         12 . The compound of  claim 10 , wherein the radionuclide is an alpha-particle or beta-particle emitter. 
     
     
         13 . The compound of  claim 10 , wherein the radionuclide is selected from the group consisting of  90 Y,  177 Lu,  18 F,  64 Cu,  67 Cu,  89 Zr,  124 I,  123 I,  152 Eu, and  99m Tc. 
     
     
         14 . The compound of  claim 10 , wherein the radionuclide is selected from the group consisting of  225 Ac,  68 Ga, and  111 In. 
     
     
         15 . A composition comprising  111 In-DOTA-MC1RL,  68 Ga-DOTA-MC1RL or  225 Ac-DOTA-MC1RL and a pharmaceutically acceptable carrier. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method of treating a cancer in a subject, comprising: administering to the subject an effective amount of a composition of comprising a compound of  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the cancer is metastatic melanoma. 
     
     
         20 . The method of  claim 18 , wherein the cancer is uveal melanoma. 
     
     
         21 . The method of  claim 18 , wherein the cancer is cutaneous melanoma.