Indazole and Benzoisoxazole Compounds as Dihydroorotate Dehydrogenase Inhibitors for Treating Acute Myelogenous Leukemia.

pubs.acs.org/acsmedchemlett Patent Highlight Indazole and Benzoisoxazole Compounds as Dihydroorotate Dehydrogenase Inhibitors for Treating Acute Myelogenous Leukemia Ram W. Sabnis* Cite This: ACS Med. Chem. Lett. 2022, 13, 763−764 ACCESS Read Online Metrics & More Article Recommendations Important Compound Classes. The present application describes a series of indazole and benzoisoxazole compounds as DHODH inhibitors that are useful for treatment of cancer, autoimmune, and inflammatory diseases, particularly for the treatment of AML. Further, Title. Indazole and Benzoisoxazole Dihydroorotate Dehydrogenase Inhibitors Patent Publication Number. WO 2021/240424 A1 URL:https://patents.google.com/patent/ WO2021240424A1/en Publication Date. December 2, 2021 Priority Application. US 63/031,815 Priority Date. May 29, 2020 Inventors. Kuduk, S.; Zhang, X. Assignee Company. Janssen Biotech Inc., USA Disease Area. Acute myelogenous leukemia (AML) Biological Target. Dihydroorotate dehydrogenase (DHODH) Summary. Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogeneous disease in that it presents with a range of cytogenetic, morphological, and immunophenotypic features and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells. Dihydroorotate dehydrogenase (DHODH) is a flavin mononucleotide (FMN) flavoprotein located in the inner mitochondrial membrane that catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis pathway. Inhibition of DHODH decreases the synthesis of pyrimidines, important precursors for nucleotide synthesis, but also the biosynthesis of glycoproteins and phospholipids. DHODH inhibition drives AML differentiation in vitro and results in dose-dependent antileukemic effects, decreased leukemic stem cells, and prolonged survival in vivo. Small-molecule DHODH inhibitors mediate antiproliferative activity against AML cells, with concomitant cell cycle arrest and induction of apoptosis. Published 2022 by American Chemical Society the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment. Definitions. Q = O or N-Rc, wherein Rc is H, CH3, or CH(CH3)3; R3 = O-R4 or NH-R4; and R5 = H, C1-3alkyl, F, or Cl. Key Structures. Received: April 2, 2022 Published: April 22, 2022 763 https://doi.org/10.1021/acsmedchemlett.2c00150 ACS Med. Chem. Lett. 2022, 13, 763−764 ACS Medicinal Chemistry Letters ■ pubs.acs.org/acsmedchemlett Patent Highlight RECENT REVIEW ARTICLES (1) Zhang, L.; Zhang, J.; Wang, J.; Ren, C.; Tang, P.; Ouyang, L.; Wang, Y. Eur. J. Med. Chem. 2022, 232, 114176. (2) Zhao, L.; Zhou, X.; Xie, F.; Zhang, L.; Yan, H.; Huang, J.; Zhang, C.; Zhou, F.; Chen, J.; Zhang, L. Cancer Commun. 2022, 42, 88. (3) Kondo, T. Semin. Cancer Biol. 2022, in press. (4) Schmidt, D. R.; Patel, R.; Kirsch, D. G.; Lewis, C. A.; Vander Heiden, M. G.; Locasale, J. W. CA Cancer J. Clin 2021, 71, 333. (5) Wang, W.; Cui, J.; Ma, H.; Lu, W.; Huang, J. Front. Oncol. 2021, 11, 684961. (6) Boukalova, S.; Hubackova, S.; Milosevic, M.; Ezrova, Z.; Neuzil, J.; Rohlena, J. Biochim. Biophys. Acta, Mol. Basis Dis. 2020, 1866, 165759. Biological Assay. In vitro DHODH enzymatic assay and in vitro MOLM-13 cellular assay were performed. The compounds described in this application were tested for their ability to inhibit DHODH and MOLM-13. The DHODH IC50 (nM) and MOLM-13 IC50 (nM) are shown in the table below. Biological Data. The table below shows representative compounds that were tested for DHODH and MOLM-13 inhibition. The biological data obtained from testing the representative examples are listed in the following table. Claims. Total claims: 14 Compound claims: 7 Pharmaceutical composition claims: 1 Method of treatment claims: 6 ■ AUTHOR INFORMATION Corresponding Author Ram W. Sabnis − Smith, Gambrell & Russell LLP, Atlanta, Georgia 30309, United States; orcid.org/0000-00017289-0581; Email: Complete contact information is available at: https://pubs.acs.org/10.1021/acsmedchemlett.2c00150 Notes The author declares no competing financial interest. 764 https://doi.org/10.1021/acsmedchemlett.2c00150 ACS Med. Chem. Lett. 2022, 13, 763−764  (...truncated)