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Recent advances in drug development have led to the establishment of several highly selective small molecule inhibitors, several of which are currently under investigation in clinical trials. These compounds allow the precise interrogation of specific chromatin features and functions, transforming the field of epigenetic cancer therapy from rather unselective approaches, like histone deacetylase inhibition or demethylating agents, toward the use of true targeted therapeutics. Recently, several compounds altering histone methylation have been investigated in preclinical and clinical trials. We summarize the current state of development for inhibitors against Menin\u2010KMT2A, DOT1L, KDM1A, and Polycomb complexes, and the arginine methyltransferase PRMT5 for the treatment of myeloid malignancies, lymphoma, and different solid tumors. Inhibitors of IDH1\/2 act at the interface of epigenetic and metabolic vulnerabilities and have been FDA\u2010approved for the treatment of IDH\u2010mutant glioma, cholangiocarcinoma, and myeloid malignancies. Several clinical trials investigating effective combination therapy regimens are ongoing and summarized herein. Drugs targeting components of SWI\/SNF chromatin remodeling complexes, such as inhibitors of SMARCA4, have entered the clinic. Members of SWI\/SNF complexes are among the most frequently mutated genes across all cancer entities, and novel selective inhibitors for the first time allow pharmacologic interrogation of aberrant chromatin remodeling. Overall, the therapeutic interrogation of chromatin\u2010related processes plays an increasing role in cancer therapy. This chapter reviews recent developments and future directions in the field of epigenetic cancer therapy.<\/jats:p>","DOI":"10.1002\/ijc.35389","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T05:12:57Z","timestamp":1743829977000},"page":"382-408","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Therapeutic targeting of chromatin alterations in leukemia and solid tumors"],"prefix":"10.1002","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-3321","authenticated-orcid":false,"given":"Florian","family":"Perner","sequence":"first","affiliation":[{"name":"Hematology, Hemostasis, Oncology and Stem Cell Transplantation Hannover Medical School (MHH)  Hannover Germany"},{"name":"DGHO, Deutsche Gesellschaft f\u00fcr H\u00e4matologie und Medizinische Onkologie e.V. 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