Peptidomimetic macrocycles and uses thereof

Abstract

Methods for treating solid tumor, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a solid tumor, determined to lack a p53 deactivation mutation, in a subject.

1 . A method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of a p53 activator, and a therapeutically-effective amount of another anticancer agent; wherein the p53 activator reduces a side effect associated with the other anticancer agent. 
     
     
         2 . The method of  claim 1 , wherein the therapeutically-effective amount of the p53 activator and the therapeutically-effective amount of the other anticancer agent synergize. 
     
     
         3 . The method of  claim 1 , wherein the therapeutically-effective amount of the other anticancer agent is lower than is a therapeutically-effective amount of the other anticancer agent in absence of the p53 activator. 
     
     
         4 . The method of  claim 1 , wherein the side effect is toxicity. 
     
     
         5 . The method of  claim 1 , wherein the p53 activator and the other anticancer agent are administered in a common pharmaceutical composition. 
     
     
         6 . The method of  claim 1 , wherein the p53 activator and the other anticancer agent are administered in separate pharmaceutical compositions. 
     
     
         7 . The method of  claim 1 , wherein the p53 activator and the other anticancer agent are administered concurrently. 
     
     
         8 . The method of  claim 1 , wherein the p53 activator and the other anticancer agent are administered sequentially. 
     
     
         9 . The method of  claim 1 , wherein the other anticancer agent is a hormonal agent, aromatase inhibitor, selective estrogen receptor modulator (SERM), estrogen receptor antagonist, chemotherapeutic agent, microtubule disassembly blocker, antimetabolite, topoisomerase inhibitor, DNA crosslinker or damaging agent, anti-antigenic agent, VEGF antagonist, receptor antagonist, integrin antagonist, vascular targeting agent (VTA), or vascular disrupting agent (VDA). 
     
     
         10 . The method of  claim 1 , wherein the other anticancer agent is a class I (camptotheca) topoisomerase inhibitor, topotecan, irinotecan, rubitecan, belotecan, a class II (podophyllum) topoisomerase inhibitor, etoposide, VP-16, teniposide, anthracyclines, doxorubicin, epirubicin, Doxil, aclarubicin, amrubicin, daunorubicin, idarubicin, pirarubicin, valrubicin, and zorubicin, anthracenediones, mitoxantrone, or pixantrone. 
     
     
         11 . The method of  claim 1 , wherein the side effect is related to a hematopoietic organ tissue. 
     
     
         12 . The method of  claim 1 , wherein the side effect is hematologic. 
     
     
         13 . The method of  claim 1 , wherein the side effect is thrombocytopenia, neutropenia, or febrile neutropenia. 
     
     
         14 . The method of  claim 1 , wherein the p53 activator binds to MDM2 and/or MDMX. 
     
     
         15 . The method of  claim 1 , wherein the p53 activator disrupts an interaction between p53 and MDM2 and/or MDMX. 
     
     
         16 . The method of  claim 1 , wherein the p53 activator is administered in a dosage of about 0.5-20 mg per kilogram body weight of the subject. 
     
     
         17 . The method of  claim 1 , wherein the therapeutically-effective amount of the p53 activator is about 0.04 mg, 0.08 mg, 0.16 mg, 0.32 mg, 0.64 mg, 1.28 mg, 3.56 mg, 7.12 mg, or 14.24 mg of the p53 activator per kilogram body mass of the subject. 
     
     
         18 . The method of  claim 1  wherein the administering is over a period of 0.25-2.0 h. 
     
     
         19 . The method of  claim 1 , wherein the p53 activator comprises an amino acid sequence which is at least about 60% identical to an amino acid sequence in any of Table 3, Table 3a, Table 3b, and Table 3c, wherein the peptidomimetic macrocycle has the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         each A, C, D and E is independently an amino acid; 
         each B is independently an amino acid, 
       
       
         
           
           
               
               
           
         
       
       [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
 each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; 
 each R 3  independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
 each L and L′ is independently a macrocycle-forming linker of the formula -L 1 -L 2 -; 
 each L 1 , L 2 , and L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ; 
 each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
 each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; 
 each R 5  is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR E , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; 
 each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; 
 each R 7  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; 
 each R 8  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
 each v is independently an integer; 
 each w is independently an integer from 3-1000; 
 u is an integer from 1-10; 
 each x, y and z is independently an integer from 0-10; and 
 each n is independently an integer from 1-5. 
 
     
     
         20 . The method of  claim 1 , wherein the p53 activator induces cell cycle arrest in the subject. 
     
     
         21 . The method of  claim 1 , wherein the cancer is non-small cell lung cancer.