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Development of Small Molecules for Acute Myeloid Leukemia Therapy

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 15677

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Special Issue Editors

Dr. Rui Su

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Guest Editor

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA
Interests: RNA epigenetics; acute myeloid leukemia; therapeutic target; drug development; cancer metabolism; cancer immunity

Dr. Ling Li

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Guest Editor

Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA, USA
Interests: leukemia stem cells; acute myeloid leukemia; chronic myeloid leukemia

Special Issue Information

Dear Colleagues,

Acute myeloid leukemia (AML) is an aggressive form of hematologic malignancy. Despite improved treatment-adapted approaches, more than 70% of AML patients have a low 5-year survival rate due to refractory or drug resistance, which warrants the identification of promising novel therapeutic targets and development of specific small molecule inhibitors. The US Food and Drug Administration (FDA) has approved small compounds targeting FLT3 mutations (Midostaurin), IDH1 mutation (ivosidenib), and IDH2 mutation (enasidenib), which provides new hope for targeted therapy as well as for the cure of AML. In addition, extensive efforts have been devoted to identifying attractive and safe druggable targets, delineating the underlying molecular mechanisms during leukemogenesis, and developing (designing) selective and effective small inhibitors for AML therapy. For instance, dysregulation of enzymes involving in epigenetic modifications (DNA methylation, histone modification, and N6-methyladenosine RNA modification) leads to leukemogenesis, and a variety of compounds targeting those enzymes have been identified for translational medicine and clinical trials. Thus, small molecule compounds represent a very promising approach for future AML treatment and precision medicine.

Dr. Rui Su
Dr. Ling Li
Guest Editors

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Keywords

acute myeloid leukemia
druggable targets
small molecule inhibitor
DNA methylation
histone modification
RNA epigenetics

Published Papers (6 papers)

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Research

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18 pages, 3313 KiB

Open AccessArticle

Role of Diacylglycerol Kinases in Acute Myeloid Leukemia

by Teresa Gravina, Chiara Maria Teresa Boggio, Elisa Gorla, Luisa Racca, Silvia Polidoro, Sara Centonze, Daniela Ferrante, Monia Lunghi, Andrea Graziani, Davide Corà and Gianluca Baldanzi

Biomedicines 2023, 11(7), 1877; https://doi.org/10.3390/biomedicines11071877 - 1 Jul 2023

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Abstract

Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DGKH expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the DGKA and DGKH isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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20 pages, 42160 KiB

Open AccessArticle

Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo

by Timur I. Fetisov, Anna A. Borunova, Alina S. Antipova, Elena E. Antoshina, Lubov S. Trukhanova, Tatyana G. Gorkova, Svetlana N. Zuevskaya, Alexei Maslov, Katerina Gurova, Andrei Gudkov, Ekaterina A. Lesovaya, Gennady A. Belitsky, Marianna G. Yakubovskaya and Kirill I. Kirsanov

Biomedicines 2023, 11(1), 230; https://doi.org/10.3390/biomedicines11010230 - 16 Jan 2023

Cited by 1 | Viewed by 2683

Abstract

The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137’s cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2/M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-V/PI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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16 pages, 3227 KiB

Open AccessArticle

NPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibition

by Anette Lodvir Hemsing, Kristin Paulsen Rye, Kimberley Joanne Hatfield and Håkon Reikvam

Biomedicines 2022, 10(8), 1881; https://doi.org/10.3390/biomedicines10081881 - 4 Aug 2022

Cited by 5 | Viewed by 1677

Abstract

The prognosis of acute myeloid leukemia (AML) is poor, especially for the elderly population. Targeted therapy with small molecules may be a potential strategy to overcome chemoresistance and improve survival in AML. We investigated the inhibition of the signaling molecule ras-related C3 botulinum toxin substrate 1 (Rac1) in leukemia cells derived from 79 consecutive AML patients, using five Rac1 inhibitors: ZINC69391, ITX3, EHOP-016, 1A-116, and NSC23766. In vitro cell proliferation and apoptosis assays and the assessment of cytokine profiles in culture media were conducted. All five inhibitors had an antiproliferative effect; IC₅₀ ranged from 3–24 µM. They induced significant apoptosis and necrosis compared to the untreated controls (p < 0.0001) at concentrations around IC₄₀ and IC₈₀. A high versus an intermediate or low antiproliferative effect was more common in NPM1-mutated (p = 0.002) and CD34-negative (p = 0.008) samples, and when NPM1 and FLT3 (p = 0.027) were combined. Presence of NPM1 mutation was associated with reduced viability after treatment with EHOP-016 (p = 0.014), ITX3 (p = 0.047), and NSC23766 (p = 0.003). Several cytokines crucial for leukemogenesis were reduced after culture, with the strongest effects observed for 1A-116 and NSC23766. Our findings suggest potent effects of Rac1 inhibition in primary AML cells and, interestingly, samples harboring NPM1 mutation seem more vulnerable. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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Review

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16 pages, 1925 KiB

Open AccessEditor’s ChoiceReview

Targeted Therapy Development in Acute Myeloid Leukemia

by Tulasigeri M. Totiger, Anirban Ghoshal, Jenna Zabroski, Anya Sondhi, Saanvi Bucha, Jacob Jahn, Yangbo Feng and Justin Taylor

Biomedicines 2023, 11(2), 641; https://doi.org/10.3390/biomedicines11020641 - 20 Feb 2023

Cited by 12 | Viewed by 4435

Abstract

Therapeutic developments targeting acute myeloid leukemia (AML) have been in the pipeline for five decades and have recently resulted in the approval of multiple targeted therapies. However, there remains an unmet need for molecular treatments that can deliver long-term remissions and cure for this heterogeneous disease. Previously, a wide range of small molecule drugs were developed to target sub-types of AML, mainly in the relapsed and refractory setting; however, drug resistance has derailed the long-term efficacy of these as monotherapies. Recently, the small molecule venetoclax was introduced in combination with azacitidine, which has improved the response rates and the overall survival in older adults with AML compared to those of chemotherapy. However, this regimen is still limited by cytotoxicity and is not curative. Therefore, there is high demand for therapies that target specific abnormalities in AML while sparing normal cells and eliminating leukemia-initiating cells. Despite this, the urgent need to develop these therapies has been hampered by the complexities of this heterogeneous disease, spurring the development of innovative therapies that target different mechanisms of leukemogenesis. This review comprehensively addresses the development of novel targeted therapies and the translational perspective for acute myeloid leukemia, including the development of selective and non-selective drugs. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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23 pages, 1254 KiB

Open AccessReview

Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia

by Hironori Arai, Yosuke Minami, SungGi Chi, Yoshikazu Utsu, Shinichi Masuda and Nobuyuki Aotsuka

Biomedicines 2022, 10(12), 3008; https://doi.org/10.3390/biomedicines10123008 - 22 Nov 2022

Cited by 2 | Viewed by 2059

Abstract

Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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16 pages, 588 KiB

Open AccessReview

Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations

by Fangliang Zhang and Liang Chen

Biomedicines 2022, 10(8), 1972; https://doi.org/10.3390/biomedicines10081972 - 15 Aug 2022

Cited by 1 | Viewed by 2088

Abstract

Splicing factors are frequently mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations are presumed to contribute to oncogenic transformation, but the underlying mechanisms remain incompletely understood. While no specific treatment option is available for MDS/AML patients with spliceosome mutations, novel targeting strategies are actively explored, leading to clinical trials of small molecule inhibitors that target the spliceosome, DNA damage response pathway, and immune response pathway. Here, we review recent progress in mechanistic understanding of splicing factor mutations promoting disease progression and summarize potential therapeutic strategies, which, if successful, would provide clinical benefit to patients carrying splicing factor mutations. Full article

(This article belongs to the Special Issue Development of Small Molecules for Acute Myeloid Leukemia Therapy)

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