Peptidomimetic macrocycles and uses thereof

Abstract

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

1 .- 210 . (canceled) 
     
     
         211 . A method of treating a liquid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a p53 activator, wherein the p53 activator is a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, and wherein the p53 activator binds to a MDM2 or a MDMX protein. 
     
     
         212 . The method of  claim 211 , wherein the p53 activator binds to a MDM2 protein and disrupts an interaction between a p53 protein and the MDM2 protein. 
     
     
         213 . The method of  claim 211 , wherein the p53 activator binds to a MDMX protein and disrupts an interaction between a p53 protein and the MDMX protein. 
     
     
         214 . The method of  claim 211 , wherein the liquid tumor has no p53 deactivating mutation. 
     
     
         215 . The method of  claim 214 , wherein the liquid tumor expresses a wild type p53 protein. 
     
     
         216 . The method of  claim 214 , wherein the liquid tumor has a p53 gain of function mutation. 
     
     
         217 . The method of  claim 214 , further comprising determining that the liquid tumor lacks the p53 deactivating mutation prior to administering the p53 activator. 
     
     
         218 . The method of  claim 211 , wherein the administering is intravenous. 
     
     
         219 . The method of  claim 211 , wherein the administering is once every week. 
     
     
         220 . The method of  claim 211 , wherein the administering is once every 2 weeks. 
     
     
         221 . The method of  claim 211 , wherein the administering is once every 3 weeks. 
     
     
         222 . The method of  claim 211 , wherein the administering is two times a week. 
     
     
         223 . The method of  claim 211 , wherein the administering is three times a week. 
     
     
         224 . The method of  claim 211 , further comprising administering a therapeutically effective amount of at least one additional therapeutic agent to the human subject. 
     
     
         225 . The method of  claim 211 , wherein the treating causes essentially no adverse effects in a normal-hematopoietic tissue in the human subject. 
     
     
         226 . The method of  claim 211 , wherein the treating results in essentially no dose-limiting thrombocytopenia in the human subject. 
     
     
         227 . The method of  claim 211 , wherein the therapeutically effective amount is about 0.5 to about 10 mg per kilogram body weight of the human subject. 
     
     
         228 . The method of  claim 211 , wherein the liquid tumor is myelodysplastic syndrome, acute myeloid leukemia, multiple myeloma, neoplasm, or chronic myeloproliferative disorder. 
     
     
         229 . The method of  claim 211 , wherein
 (i) the liquid tumor is acute myeloid leukemia (AML), or   (ii) the liquid tumor is not a HPV positive cancer; or   (iii) the liquid tumor is peripheral T cell lymphoma; or   (iv) the liquid tumor is a myelodysplastic syndrome (MDS); or   (vi) the liquid tumor is chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, heavy chain diseases, extranodal marginal zone B cell lymphoma, malt lymphoma, nodal marginal zone B cell lymphoma (nmzl), follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, T cell prolymphocytic leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, nasal type, enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, blastic NK cell lymphoma, mycosis fungoides/sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, unspecified, anaplastic large cell lymphoma, classical Hodgkin lymphomas (nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte depleted or not depleted), or nodular lymphocyte-predominant Hodgkin lymphoma.   
     
     
         230 . A pharmaceutical composition comprising a p53 activator for treating a liquid tumor in a human subject in need thereof, wherein the p53 activator is a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, wherein the p53 activator binds to a MDM2 or a MDMX protein.