First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent

Farag, Ahmed Karam; Hassan, Ahmed H.E.; Jeong, Hyeanjeong; Kwon, Yong Dae; Choi, Jin Gyu; Oh, Myung Sook; Park, Ki Duk; Kim, Yun Kyung; Roh, Eun Joo

doi:10.1016/j.ejmech.2018.10.057

Cited by 28 publications

(19 citation statements)

References 57 publications

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“…This inhibitor has a promising inhibitory effect on DAPK1 (IC 50 = 0.03 μM) and is highly selective for the ATP binding sites and substrate recognition motifs, including Gly-Glu-Leu (GEL) and Pro-Glu-Asn (PEN) [137]. More recently, dual inhibitors targeting DAPK1 as well as macrophage colony-stimulating factor 1 receptor (CSF1R) have been developed as potential agents to inhibit tau aggregates and neuroinflammation [138]. CSF1R plays a role in regulating the survival and proliferation of microglial cells, and its inhibition leads to a reduction of neuroinflammation and neuronal damage [138].…”

Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

“…More recently, dual inhibitors targeting DAPK1 as well as macrophage colony-stimulating factor 1 receptor (CSF1R) have been developed as potential agents to inhibit tau aggregates and neuroinflammation [138]. CSF1R plays a role in regulating the survival and proliferation of microglial cells, and its inhibition leads to a reduction of neuroinflammation and neuronal damage [138]. The dual inhibitor compound 31 (3,5-dimethoxy- N -(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide), is a unique and selective inhibitor of both DAPK1 (IC 50 = 1.25 μM) and CSF1R (IC 50 = 0.15 μM) [138].…”

Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

“…CSF1R plays a role in regulating the survival and proliferation of microglial cells, and its inhibition leads to a reduction of neuroinflammation and neuronal damage [138]. The dual inhibitor compound 31 (3,5-dimethoxy- N -(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide), is a unique and selective inhibitor of both DAPK1 (IC 50 = 1.25 μM) and CSF1R (IC 50 = 0.15 μM) [138]. More importantly, it has high blood-brain barrier (BBB) permeability in the absence of toxicity and significantly decreases tau aggregation (IC 50 = 5.0 μM) in vitro [138].…”

Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

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Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

Kim

Chen

Zhou

et al. 2019

IJMS

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Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases.

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Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Dapk1 As a Potential Target For Neurodegenerative Diseasesmentioning

confidence: 99%

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Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

Kim

Chen

Zhou

et al. 2019

IJMS

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“…The ligand was sketched, hydrogens added, energy minimized and saved as mol2 files. SwissDock which is based on the docking software EADock DSS running on the Vital-IT cluster was used to dock TMS-TMF-4f to the crystal structures (PDB codes: 3cwg and 1bg1, indicating unphosphorylated STAT3 and phosphorylated DNA-bound STAT3, respectively) in accurate mode as a blind docking study [46][47][48].…”

Section: Molecular Docking Analysismentioning

confidence: 99%

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

Hong

Chung

Shin

et al. 2019

Cancers

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We previously reported the potential anti-proliferative activity of 3-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-N-(3,4,5-trimethoxyphenyl) benzamide (TMS-TMF-4f) against human cancer cells; however, the underlying molecular mechanisms have not been investigated. In the present study, TMS-TMF-4f showed the highest cytotoxicity in human cervical cancer cells (HeLa and CaSki) and low cytotoxicity in normal ovarian epithelial cells. Annexin V-FITC and propidium iodide (PI) double staining revealed that TMS-TMF-4f-induced cytotoxicity was caused by the induction of apoptosis in both HeLa and CaSki cervical cancer cells. The compound TMS-TMF-4f enhanced the activation of caspase-3, caspase-8, and caspase-9 and regulated Bcl-2 family proteins, which led to mitochondrial membrane potential (MMP) loss and resulted in the release of cytochrome c and Smac/DIABLO into the cytosol. Also, TMS-TMF-4f suppressed both constitutive and IL-6-inducible levels of phosphorylated STAT3 (p-STAT3) and associated proteins such as Mcl-1, cyclin D1, survivin, and c-Myc in both cervical cancer cells. STAT-3 overexpression completely ameliorated TMS-TMF-4f-induced apoptotic cell death and PARP cleavage. Docking analysis revealed that TMS-TMF-4f could bind to unphosphorylated STAT3 and inhibit its interconversion to the activated form. Notably, intraperitoneal administration of TMS-TMF-4f (5, 10, or 20 mg/kg) decreased tumor growth in a xenograft cervical cancer mouse model, demonstrated by the increase in TUNEL staining and PARP cleavage and the reduction in p-STAT3, Mcl-1, cyclin D1, survivin, and c-Myc expression levels in tumor tissues. Taken together, our results suggest that TMS-TMF-4f may potentially inhibit human cervical tumor growth through the induction of apoptosis via STAT3 suppression.

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“…Thus, in addition to the 4-phenoxy feature shared by both hit compound 4 and WZ4002, the offspring molecules ( 6 , Figure 1) would also inherit the 5-benzamide feature from hit compound 4 and the 2-anilino feature from WZ4002. Noteworthy, some recently reported non-ATP-competitive DAPK1, ATP-competitive CSF1R kinases dual inhibitors for the treatment of the neurodegenerative tauopathies possess similar structures to this design rationale even though they were designed via different approach and for a different therapeutic purpose 16 . Therefore, reprofiling the bioactivity of such compounds against cancer cells was strongly encouraged.…”

Section: Introductionmentioning

confidence: 99%

Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds

Farag

Hassan

Ahn

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC50 value of 1.97 µM against M-NFS-60 cells and good GIT absorption with Pe value of 19.0 ± 1.1 × 10−6 cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.

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First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent

Cited by 28 publications

References 57 publications

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds

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