Dual FLT3/TOPK Inhibitor with Activity against FLT3-ITD Secondary Mutations Potently Inhibits Acute Myeloid Leukemia Cell Lines

Dayal, Neetu; Opoku‐Temeng, Clement; Hernandez, Delmis E; Sooreshjani, Moloud Aflaki; Carter-Cooper, Brandon; Lapidus, Rena G.; Sintim, Herman O.

doi:10.4155/fmc-2017-0298

Cited by 18 publications

(25 citation statements)

References 30 publications

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“…Combining FLT3 inhibitors with other agents is the major drive in the clinical trials to overcome the resistance to current FLT3 TKIs. Dayal successfully used a collaborative FLT3 inhibitor, HSD 1169, to act against FLT3/ITD and sorafenib-resistant cell lines [ 86 ]. In a recent report, PI3K-delta inhibitor had synergistic anti-tumor activity with FLT3 inhibitors [ 87 ].…”

Section: Introductionmentioning

confidence: 99%

“…By integrating these novel inhibitors in combination with FLT3 inhibitors, their efficacy may be further improved in the near future. Bispecific antibodies, immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells are major modalities of novel cancer immunotherapy [ 86 – 102 ]. Crenolanib was already shown to have synergistic activity with FLT3-targeted CAR T cells [ 67 ].…”

Section: Introductionmentioning

confidence: 99%

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FLT3 inhibitors in acute myeloid leukemia

2018

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FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FLT3 inhibitors in acute myeloid leukemia

2018

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“…This work adds to literature examples whereby multicomponent reactions have been used to make libraries that contain potent anticancer agents with nanomolar activities. 10 , 38 − 41 …”

Section: Discussionmentioning

confidence: 99%

HSD1787, a Tetrahydro-3H-Pyrazolo[4,3-f]Quinoline Compound Synthesized via Povarov Reaction, Potently Inhibits Proliferation of Cancer Cell Lines at Nanomolar Concentrations

2020

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Multicomponent reaction (MCR) is often used to rapidly assemble complex compounds for drug screening. Povarov MCR has been used to prepare a new library containing tetrahydro-3 H -pyrazolo[4,3- f ]quinoline core and the library tested against MDA-MB-231 (a triple-negative breast cancer, TNBC, cell line). A few of the tetrahydro-3 H -pyrazolo[4,3- f ]quinoline-containing compounds, bearing 3-aminoindazolyl group, potently inhibited MDA-MB-231. The most active compound, HSD1787, was evaluated against NCI60 cell lines and this compound inhibited melanoma, renal, breast, ovarian, and leukemia cancer cell lines with GI 50 values as low as 0.1 μM. The tetrahydro-3 H -pyrazolo[4,3- f ]quinoline core is therefore a new scaffold that could be developed into potent anticancer therapeutics against difficult-to-treat cancers.

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“…Cell culture, chemicals, plasmids, primers, and antibodies AML cells were maintained in RPMI 1640 with 10% fetal bovine serum. Kasumi-1, U937, SKNO-1, and THP-1 cells have been described previously (18), and the HL-60 cell line was a gift from Herman Sintim (55). Lentiviral particles were produced in HEK293T cells as described previously (39).…”

Section: Methodsmentioning

confidence: 99%

The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid–induced myeloid gene expression and differentiation in acute myeloid leukemia

Steinauer

Guo

Zhang

2020

Journal of Biological Chemistry

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CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3, also known as MTG16 or ETO2) is a myeloid translocation gene family protein that functions as a master transcriptional corepressor in hematopoiesis. Recently, it has been shown that CBFA2T3 maintains leukemia stem cell gene expression and promotes relapse in acute myeloid leukemia (AML). However, a role for CBFA2T3 in myeloid differentiation of AML has not been reported. Here, we show that CBFA2T3 represses retinoic acid receptor (RAR) target gene expression and inhibits all-trans-retinoic acid (ATRA)-induced myeloid differentiation of AML cells. ChIP-Seq revealed that CBFA2T3 targets the RARα/RXRα cistrome in U937 AML cells, predominantly at myeloid-specific enhancers associated with terminal differentiation. CRISPR/Cas9-mediated abrogation of CBFA2T3 resulted in spontaneous and ATRA-induced activation of myeloid-specific genes in a manner correlated with myeloid differentiation. Importantly, these effects were reversed by CBFA2T3 re-expression. Mechanistic studies showed that CBFA2T3 inhibits RAR target gene transcription by acting at an early step to regulate histone acetyltransferase recruitment, histone acetylation, and chromatin accessibility at RARα target sites, independently of the downstream, RAR-mediated steps of transcription. Finally, we validated the inhibitory effect of CBFA2T3 on RAR in multiple AML subtypes and patient samples. To our knowledge, this is the first study to show that CBFA2T3 down-regulation is both necessary and sufficient for enhancing ATRA-induced myeloid gene expression and differentiation of AML cells. Our findings suggest that CBFA2T3 can serve as a potential target for enhancing AML responsiveness to ATRA differentiation therapies.

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Dual FLT3/TOPK Inhibitor with Activity against FLT3-ITD Secondary Mutations Potently Inhibits Acute Myeloid Leukemia Cell Lines

Abstract: HSD1169 or an analog could become a therapeutic agent for AML containing drug-resistant FLT3-ITD.

Cited by 18 publications

References 30 publications

FLT3 inhibitors in acute myeloid leukemia

FLT3 inhibitors in acute myeloid leukemia

HSD1787, a Tetrahydro-3H-Pyrazolo[4,3-f]Quinoline Compound Synthesized via Povarov Reaction, Potently Inhibits Proliferation of Cancer Cell Lines at Nanomolar Concentrations

The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid–induced myeloid gene expression and differentiation in acute myeloid leukemia

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