Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms

Abstract

Herein, we describe the design, synthesis, and structure−activity relationships of a series of unique 4-(1Hpyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that 18e was a preferred compound, with IC 50 values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover, 18e was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, 18e exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of 18e could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally, 18e showed an excellent bioavailability (F = 58%), a suitable half-life time (T 1/2 = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that 18e might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia. ■ INTRODUCTIONJanus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases (JAK1, JAK2, JAK3, and TYK2). The JAK-signal transducer and activator of the transcription (JAK−STAT) pathway mediates signaling by cytokines, which controls the survival, proliferation, and differentiation of a variety of cells. 1−4 JAK2 phosphorylation, downstream STAT phosphorylation, and activation of gene transcription ultimately result in increased proliferation, differentiation, and survival of erythroid and myeloid cells. 5 Among the four JAK subtypes, JAK2 was proven to be critical for the growth and progression of hematologic malignancies, especially for myeloproliferative neoplasms (MPNs). 6 Activating JAK2 fusion proteins has been also described in chronic myelogenous leukemia, 7,8 acute myelocytic leukemia (AML), 9 and acute lymphoblastic leukemia. 10 Currently, a number of pan JAK and selective JAK inhibitors, such as ruxolitinib, a JAK1/2 inhibitor, used for myelofibrosis, 11,12 tofacitinib, a JAK1/JAK3 inhibitor used for rheumatoid arthritis, 13 and fedratinib, a JAK2/FLT3 inhibitor used for myelofibrosis in Aug 2019, 14 have been used clinically.FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that plays a crucial role in the development of hematopoietic progenitor cells. 15 Up to 20−30% of patients with AML have been shown to have an activated FLT3 internal tandem duplication (ITD) mutation, which is a high-risk factor for disease relapse. 16−18 To date, several small-molecule inhibitors against FLT3, 19 such as midostaurin (PKC412, approved for AML by the FDA), 20,21 quizartinib (AC220, approved for AML in Japan in 2019), 22 and gilteritinib (ASP2215, approved for AML by the FDA in 2018) have been developed. 23 Although positive outcomes were obtained for thes...

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“…FM, a potent and highly selective JAK2 and FLT3 inhibitor, was designed and synthesized in our laboratory [ 35 ] (Fig. 1A ).…”

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