HM43239, a Novel Potent Small Molecule FLT3 Inhibitor, in Acute Myeloid Leukemia (AML) with FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1 /2 Study

Daver, Naval; Lee, Kyoo Hyung; Yoon, Sung‐Soo; Jung, Chul Won; Kang, Hyun Jeong; Jung, S. Y.; Seo, Sujin; Yoon, Jiyeon; Kim, Hyun‐Jin; Noh, Young Su; Seo, Yoonha; Kwon, Hye-Jin; Han, Oakpil; Baek, Seung Jae; Seo, Kyounghee; Suh, Kwee Hyun

doi:10.1182/blood-2019-129670

Cited by 5 publications

(20 citation statements)

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“…In pre-clinical studies, FF-10101 demonstrated potent activity against quizartinib-resistant AL and gatekeeper F691 mutations (118). Other agents in development include TTT-3002, G-749, MZH-29, and HM43239, all highly selective FLT3 inhibitors with activity against D835 and F691 residues (119)(120)(121)(122). In preclinical studies, these agents have demonstrated activity against AML blasts resistant to sorafenib and quizartinib (119) or midostaurin and quizartinib (120), and may represent options for refractory disease.…”

Section: Novel Flt3 Inhibitorsmentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

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Section: Novel Flt3 Inhibitorsmentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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“…Compound 11, which contains the 1H-pyrazol-3-yl as opposed to the 1H-pyrazol-4-yl in lead compound 8, showed a significant decrease in FLT3 inhibition (28.3 � 0.8 %). The -NEt substitution (13) showed similar inhibitory activity against FLT3 (59.1 � 2.9 %) compared to lead compound 8, but less selectivity over c-KIT and KDR. Other modifications to the pyrazole, including addition of a nitrile moiety (12) and a morpholine ring (14), also resulted in loss of FLT3 inhibition.…”

Section: Biological Activity and Target Engagementmentioning

confidence: 91%

“…[8][9][10] Currently, three FLT3 inhibitors have been approved by the FDA: gilteritinib, quizartinib and midostaurin, but other approved kinase inhibitors, such as sorafenib (KDR inhibitor) or ponatinib (ABL1 inhibitor) are also FLT3 inhibitors and could be used offlabel. [11][12][13][14] Other FLT3 inhibitors, such as crenolanib, tandutinib, FF-10101, and tuspetinib (Figure 1) have also been evaluated in the clinic. [11][12][13] Some of these FLT3 inhibitors have been moderately successful in increasing survival rates of patients with AML, but often dose-limiting toxicities hinder efficacy, especially in elderly patients, vide supra.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] Other FLT3 inhibitors, such as crenolanib, tandutinib, FF-10101, and tuspetinib (Figure 1) have also been evaluated in the clinic. [11][12][13] Some of these FLT3 inhibitors have been moderately successful in increasing survival rates of patients with AML, but often dose-limiting toxicities hinder efficacy, especially in elderly patients, vide supra. [15] One of the factors that accounts for dose-limiting toxicities of current FLT3 inhibitors is target promiscuity, especially targets that are critical for essential functions.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Selective FLT3 Inhibitor with Low Activity against VEGFR, FGFR, PDGFR, c‐KIT, and RET Anti‐Targets

Akwata,

Kempen,

Dayal

et al. 2023

ChemMedChem

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FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely‐related kinases that are important for immune (c‐KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non‐oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti‐targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c‐KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well‐tolerated FLT3 therapeutics for non‐oncology indications or for maintenance therapy for AML.

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“…HM43239, a novel reversible small-molecule type I FLT3 inhibitor with activity against WT-FLT3, FLT3-ITD, FLT3-TKD, and also FLT3 ITD/TKD double mutations showed in vitro (WT-FLT3 and mutant FLT3 cell lines) and in vivo (FLT3 ITD/TKD double mutated xenograft mouse model) efficacy via inhibiting STAT5, ERK, SYN, JAK1/2, and TAK1 kinases, which resulted in a currently recruiting phase I/II clinical trial (NCT03850574) to evaluate its appropriate doses and safety in R/R FLT3 AML. 173 MZH29, a novel FLT3i, showed inhibitory activity against WT, FLT3-ITD, FLT3-D835H/Y/V, and FLT3-K663Q mutants and FLT3-ITD/F691L double mutation. 174 LT-171-861, a novel FLT3i, bound to FLT3 strongly and inhibited the growth of FLT3 mutant cell lines such as FLT3-D835Y, FLT3-ITD-N676D, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-Y842C and AML blasts from patients with FLT3-ITD.…”

Section: Designing Novel Flt3imentioning

confidence: 99%

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

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HM43239, a Novel Potent Small Molecule FLT3 Inhibitor, in Acute Myeloid Leukemia (AML) with FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1 /2 Study

Cited by 5 publications

References 0 publications

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Identification of a Selective FLT3 Inhibitor with Low Activity against VEGFR, FGFR, PDGFR, c‐KIT, and RET Anti‐Targets

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

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