CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells

Tariq, Muhammad Usama; Furqan, Muhammad; Parveen, Hira; Ullah, Rahim; Muddassar, Muhammad; Saleem, Rahman Shah Zaib; Bavetsias, Vassilios; Linardopoulos, Spiros; Faisal, Amir

doi:10.1038/s41416-021-01527-2

Cited by 11 publications

(17 citation statements)

References 44 publications

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“…For FLT3, potency dropped from 76% inhibition with compound 6 at 50 nM to only 14% inhibition with compound 7. Replacing the imidazole unit in compound 6 with other 5-membered bioisosteres (triazole (8), tetrazole (10) or thiazole (13)) afforded compounds that could inhibit both kinases and AML cell proliferation, but generally less so than compound 6. Extending the length of carbon chain between the amide and the imidazole by one unit to give compound 15 did not drastically impact inhibition of either kinase.…”

Section: Kinase Assay and Structure-activity Relationship (Sar) Studymentioning

confidence: 99%

“…For example, CCT245718, a dual FLT3/Aurora A inhibitor could overcome FLT3-D835Y-mediated resistance. 13 In another interesting report, it was shown that the frequency of resistance to a dual FLT3/CDK4 inhibitor (AMG 925) was less than other FLT3 inhibitors (such as quizartinib) that did not inhibit CDK4. 14 Considering these prior dual inhibitors, we became interested in identifying FLT3 inhibitors that also inhibited other kinases which play important roles in cancer progression.…”

Section: Introductionmentioning

confidence: 99%

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Dual FLT3/haspin kinase inhibitor based on 3H-pyrazolo[4,3-f]quinoline scaffold with activities against acute myeloid leukemia

Kempen,

Brauer,

Sintim

2023

RSC Med. Chem.

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Section: Kinase Assay and Structure-activity Relationship (Sar) Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dual FLT3/haspin kinase inhibitor based on 3H-pyrazolo[4,3-f]quinoline scaffold with activities against acute myeloid leukemia

Kempen,

Brauer,

Sintim

2023

RSC Med. Chem.

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“… 176 CCT24571, a dual FLT3/Aurora A inhibitor showed cytotoxic and apoptotic effects on FLT3-ITD carrying MOLM-13 and MV4-11 AML cells and reversed D835Y resistance in vitro. 177 Another FLT3/Aurora A inhibitor, CCT241736, inhibited tumor growth of FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models and also showed efficacy in primary patient samples with quizartinib resistance. 178 AMG925, a novel dual inhibitor of FLT3/CDK4-6 induced apoptosis in both WT and mutant FLT3 AML cell lines and primary blasts.…”

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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“…Concomitantly targeting AURK and FLT3 exhibited potent cytotoxicity with lower half-maximal inhibitory concentrations (IC 50 s) values against FLT3-ITD-mutant MV4-11, MOLM13 and MOLM13-resistant AML cells. The latter harbor ITD and D835Y dual mutations (24,25). Interestingly, Druker's group recently identi ed aurora kinase B as an early resistance factor to FLT3 inhibition (26).…”

Section: Introductionmentioning

confidence: 99%

The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and Aurora kinases

Zhang

et al. 2023

Preprint

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Background: Despite the development of several FLT3 inhibitors that have improved outcomes in patients with FLT3-mutant acute myeloid leukemias (AML), drug resistance is frequently observed, which may be associated with the activation of additional pro-survival pathways such as those regulated by BTK, aurora kinases, and potentially others in addition to acquired tyrosine kinase domains (TKD) mutations of FLT3 gene. FLT3may not always be a driver mutation. Objective: To evaluate the anti-leukemia efficacy of the novel multi-kinase inhibitor CG-806, which targets FLT3 and other kinases, in order to circumvent drug resistance and target FLT3 wild-type (WT) cells. Methods: The anti-leukemia activity of CG-806 was investigated by measuring apoptosis induction and analyzing cell cycle with flow cytometry in vitro, and its anti-leukemia Results: CG-806 demonstrated superior anti-leukemia efficacy compared to commercially available FLT3 inhibitors, both in vitro and in vivo, regardless of FLT3 mutational status. The mechanism of action of CG-806 may involve its broad inhibitory profile of FLT3, BTK, and aurora kinases. InFLT3 mutant cells, CG-806 induced G1 phase blockage, while in FLT3WT cells, it resulted in G2/M arrest. Targeting FLT3 and Bcl-2 and/or Mcl-1 simultaneously resulted in a synergistic pro-apoptotic effect in FLT3mutant leukemia cells. Conclusion: The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemia efficacy, regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).

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CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells

Cited by 11 publications

References 44 publications

Dual FLT3/haspin kinase inhibitor based on 3H-pyrazolo[4,3-f]quinoline scaffold with activities against acute myeloid leukemia

Dual FLT3/haspin kinase inhibitor based on 3H-pyrazolo[4,3-f]quinoline scaffold with activities against acute myeloid leukemia

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

The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and Aurora kinases

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