Update on glasdegib in acute myeloid leukemia – broadening horizons of Hedgehog pathway inhibitors

Abstract

Numerous new emerging therapies, including oral targeted chemotherapies, have recently entered the therapeutic arsenal against acute myeloid leukemia (AML). The significant shift toward the use of these novel therapeutics, administered either alone or in combination with intensive or low-intensity chemotherapy, changes the prospects for the control of this disease, especially for elderly patients. Glasdegib, an oral Hedgehog pathway inhibitor, showed satisfactory response rates associated with moderate toxicity and less early mortality than standard induction regimens in this population. It was approved in November 2018 by the FDA and in June 2020 by the EMA for use in combination with low-dose cytarabine as a treatment of newly-diagnosed AML in patients aged ≥ 75 and/or unfit for intensive induction chemotherapy. The current paper proposes an extensive, up-to-date review of the preclinical and clinical development of glasdegib. Elements of its routine clinical use and the landscape of ongoing clinical trials are also stated.

Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue

“…Glasdegib (Figure 1), 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (previously also known as PF-04449913), was developed by Pfizer for the treatment of AML [16][17][18][19]. Glasdegib inhibits the hedgehog signaling pathway, known to be associated with a broad range of cancers, via the binding to and inhibition of transmembrane protein Smoothened [17,[19][20][21][22][23]. It was approved in November 2018 by the U.S. Food and Drug Administration and in June 2020 by the European Medicines Agency for use, in combination with low-dose cytarabine, as a treatment for newly diagnosed AML in patients aged ≥75 and/or unfit for intensive induction chemotherapy [20][21][22][23].…”