Peptidomimetic macrocycles and uses thereof

A method of antagonizing the activity of MDM2 and MDMX in a subject with cancer comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle and an additional pharmaceutically active agent, wherein combination of the peptidomimetic macrocycle and the additional pharmaceutically active agent is synergistic, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, 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-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-],
• each R1 and R2 is independently hydrogen, 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 R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, optionally substituted with R5;
• each L and L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• each L1, L2, and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;
• each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R7 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• each R8 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• each v is independently an integer from 1-1000;
• each w is independently an integer from 1-1000;
• 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,
• or pharmaceutically acceptable salt thereof,
• wherein the peptidomimetic macrocycle is not a peptidomimetic macrocycle of Tables 2a or 2b, with the proviso that the additional pharmaceutically active agent is not a nucleoside metabolic inhibitor.