The purpose of the study is to determine whether once-daily dosing with ENMD-2076 will be a safe and effective treatment in patients with FLC. Safety will be measured by looking at the adverse events that may happen and the efficacy will look at the progression of the disease over time.

Start Date01 Oct 2015

Sponsor / Collaborator

CASI Pharmaceuticals, Inc.

CTR20150075

/ RecruitingPhase 2

一项ENMD-2076治疗局部复发或转移的三阴性乳腺癌晚期患者的安全性和耐受性的IIa期临床试验

[Translation] A Phase IIa clinical trial to evaluate the safety and tolerability of ENMD-2076 in patients with locally recurrent or metastatic advanced triple-negative breast cancer

主要目的：通过三阴性乳腺癌受试者口服一定剂量的ENMD-2076，观察不良事件（AEs）发生的频率和严重程度，评估ENMD-2076的安全性和耐受性，在中国患者人群中确定合适剂量, 进而确定Ⅱb期临床试验治疗剂量。次要目的: 观察肿瘤变化和疾病进展，评价治疗的临床受益率。通过对肿瘤组织标本和血液样品进行基因外显子全序列的分析，评价其与ENMD-2076的药效相关性。

[Translation]

Primary purpose: To observe the frequency and severity of adverse events (AEs) by oral administration of a certain dose of ENMD-2076 to subjects with triple-negative breast cancer, evaluate the safety and tolerability of ENMD-2076, determine the appropriate dose in the Chinese patient population, and then determine the treatment dose for the Phase IIb clinical trial. Secondary purpose: To observe tumor changes and disease progression and evaluate the clinical benefit rate of treatment. By analyzing the full sequence of gene exons in tumor tissue specimens and blood samples, evaluate their correlation with the efficacy of ENMD-2076.

Start Date24 Mar 2015

Sponsor / Collaborator

Alcami Carolinas Corp.

[+2]

NCT01914510

/ CompletedPhase 2IIT

Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas

This is a phase 2 study to see how useful, safe, and tolerable an investigational drug called ENMD-2076 is in treating patients with ovarian clear cell carcinomas.
ENMD-2076 is an oral drug that works by blocking certain enzymes called Aurora A and tyrosine kinase from working. These enzymes are needed for cells to divide including cancer cells. ENMD-2076 also works by stopping the growth of new blood vessels which would provide the tumor with nutrients for it to grow. It is believed that by blocking Aurora A and tyrosine kinase enzymes from working and stopping new blood vessels from growing, the tumors may stop growing or shrink.

Start Date01 Sep 2013

Sponsor / Collaborator

University Health Network

100 Clinical Results associated with Aurora A x FLT3

100 Translational Medicine associated with Aurora A x FLT3

0 Patents (Medical) associated with Aurora A x FLT3

Literatures (Medical) associated with Aurora A x FLT3

01 Aug 2023·Pathophysiology : the official journal of the International Society for Pathophysiology

Shift of N-MYC Oncogene Expression in AML Patients Carrying the FLT3-ITD Mutation.

Article

Author: Girshova, Larisa ; Lomaia, Elza ; Zaritskey, Andrey ; Kudryavtseva, Ekaterina ; Fomicheva, Yulia ; Churkina, Irina ; Osipov, Yuri ; Bogdanov, Konstantin

Mutations in the FLT3 gene not only lead to abnormalities in its structure and function, but also affect the expression of other genes involved in leukemogenesis. This study evaluated the expression of genes that are more characteristic of neuroblastoma but less studied in leukemia. N-MYC oncogene expression was found to be more than 3-fold higher in primary AML patients carrying the FLT3-ITD mutation compared to carriers of other mutations as well as patients with normal karyotype (p = 0.03946). In contrast to the expression of several genes (C-MYC, SPT16, AURKA, AURKB) directly correlated to the allelic load of FLT3-ITD, the expression of the N-MYC oncogene is extremely weakly related or independent of it (p = 0.0405). Monitoring of N-MYC expression in some patients with high FLT3-ITD allelic load receiving therapy showed that a decrease in FLT3-ITD allelic load is not always accompanied by a decrease in N-MYC expression. On the contrary, N-MYC expression may remain elevated during the first three months after therapy, which is additional evidence of the emergence of resistance to therapy and progression of AML.

01 Dec 2021·Bioorganic ChemistryQ2 · CHEMISTRY

Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia

Q2 · CHEMISTRY

Article

Author: Ewies, Ewies F ; El-Sayed, Naglaa F ; El-Hussieny, Marwa ; Fouad, Marwa A

Series of novel sulfonamide-based 3-indolinones 3a-m and 4a-f were designed, synthesized and then their cytotoxic activity was evaluated against a panel of sixty cancer cell lines. This screening indicated that 4-(2-(5-fluoro-2-oxoindolin-3-ylidene)acetyl)phenyl benzenesulfonate (4f) possessed promising cytotoxicity against CCRF-CEM and SR leukemia cell lines with IC₅₀ values 6.84 and 2.97 µM, respectively. Further investigation of the leukemic cytotoxicity of compound 4f was carried out by performing PDGFRα, VEGFR2, Aurora A/B and FLT3 enzyme assays and CCRF-CEM and SR cell cycle analysis. These investigations showed that compound 4f exhibited pronounced dual inhibition of both kinases PDGFRα and Aurora A with potency of 24.15 and 11.83 nM, respectively. The in vitro results were supported by molecular docking studies in order to explore its binding affinity and its key amino acids interactions. This work represents compound 4f as a promising anticancer agent against leukemia.

28 Sep 2021·British Journal of CancerQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

BACKGROUNDActivating mutations in the Fms-like tyrosine kinase 3 (FLT3) are among the most prevalent oncogenic mutations in acute myeloid leukaemia. Inhibitors selectively targeting FLT3 kinase have shown promising clinical activity; their success in the clinic, however, has been limited due to the emergence of acquired resistance.METHODSCCT245718 was identified and characterised as a dual Aurora A/FLT3 inhibitor through cell-based and biochemical assays. The ability of CCT245718 to overcome TKD-mediated resistance was evaluated in a cell line-based model of drug resistance to FLT3 inhibitors.RESULTSCCT245718 exhibits potent antiproliferative activity towards FLT3-ITD + AML cell lines and strongly binds to FLT3-ITD and TKD (D835Y) mutants in vitro. Activities of both FLT3-ITD and Aurora A are also inhibited in cells. Inhibition of FLT3 results in reduced phosphorylation of STAT5, downregulation of survivin and induction of apoptotic cell death. Moreover, CCT245718 overcomes TKD-mediated resistance in a MOLM-13-derived cell line containing FLT3 with both ITD and D835Y mutations. It also inhibits FLT3 signalling in both parental and resistant cell lines compared to FLT3-specific inhibitor MLN518, which is only active in the parental cell line.CONCLUSIONSOur results demonstrate that CCT245718 is a potent dual FLT3/Aurora A inhibitor that can overcome TKD-mediated acquired resistance.

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