Identification, synthesis and evaluation of CSF1R inhibitors using fragment based drug design

Machiraju, Pavan Kumar; Poornachandra, Y.; Gubbala, Satya Prakash; Bohari, Taher; Abdul, Jaleel K.V.; Xu, Shili; Patel, Rahul V.; Chittireddy, Venkata Ramana Reddy; Boppana, Kiran; Jagarlapudi, Sarma A.R.P.; Neamati, Nouri; Syed, Rabbani; Amanchy, Ramars

doi:10.1016/j.compbiolchem.2019.04.015

Cited by 9 publications

(7 citation statements)

References 45 publications

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“…[ 62 , 63 ] Consequently, CSF-1R-targeting agents can be applied as promising therapies for malignant tumors. [ 61 , 64 , 65 ]…”

Section: Discussionmentioning

confidence: 99%

Overexpression of macrophage-colony stimulating factor-1 receptor as a prognostic factor for survival in cancer

Hao

et al. 2021

Medicine

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Background: The relation between the expression of macrophage-colony stimulating factor-1 receptor (CSF-1R) and prognosis of cancer patients has been evaluated in multiple studies, but the results remain controversial. We, therefore, performed a meta-analysis and systematic review to figure out the role of CSF-1R in the prognosis of patients with cancer. Methods: Several databases were searched, including Web of Science, PubMed, and EMBASE. All human studies were published as full text. The Newcastle–Ottawa risk of bias scale was applied to evaluate the research. We extracted hazard ratios (HRs) with 95% confidence interval (95% CI) which assessed progression-free survival (PFS) and overall survival (OS) in order to assess the impacts of CSF-1R on the prognosis of cancer patients. Results: A total of 12 citations were identified, with studies including 2260 patients in different cancer types that met the eligibility criteria. It was suggested in a pooled analysis that the over-expression of CSF-1R was significantly related to worse PFS (HR: 1.68; P < .001, 1.25–2.10, 95% CI) and also poorer OS (HR=1.28; P < .001, 1.03–1.54, 95% CI). Analysis in subgroups indicated over-expressed CSF-1R was significantly associated with worse OS in hematological malignancy (HR = 2.29; P < .001, 1.49–3.09, 95% CI; model of fixed-effects; I 2 = 0.0%, P < .001). Sensitivity analysis suggested that there was no study influencing the stability of the results. Conclusions: The overexpression of CSF-1R was significantly predictive of worse prognosis in those who suffer from different kinds of malignancies, particularly in hematological malignancy, which indicates that it might be a potential biomarker of prognosis in cancer survival and a potential molecular target in the treatment of malignant tumors.

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“…[ 62 , 63 ] Consequently, CSF-1R-targeting agents can be applied as promising therapies for malignant tumors. [ 61 , 64 , 65 ]…”

Section: Discussionmentioning

confidence: 99%

Overexpression of macrophage-colony stimulating factor-1 receptor as a prognostic factor for survival in cancer

Hao

et al. 2021

Medicine

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“…Availability of biochemical or biophysical assays to understand SAR is critical in hit-to-lead step. This strategy has been proven to be successful in numerous targets such as developing bacterial Gyrase B inhibitors (Figure 2; Colony-stimulating factor 1 Computational approach Machiraju et al, 2019 Bruton's Tyrosine Kinase Mass spectrometry Hopkins et al, 2019 The atypical protein kinase C-iota Thermal shift assay Kwiatkowski et al, 2018Kwiatkowski et al, , 2019 Latency-associated nuclear antigen SPR, DSF Kirsch et al, 2019 Monoamine oxidase X-ray crystallography Cheng et al, 2019 Myeloid cell leukemia 1 NMR Murray J.B. et al, 2019;Szlávik et al, 2019 β-ketoacyl-ACP synthases X-ray crystallography Patterson et al, 2020 VEGFR-2 Computational design Zhang et al, 2019 West Nile viral protease STD-NMR Schöne et al, 2017 Transcriptional repressor EthR2…”

Section: Growing Of Fragment Hitsmentioning

confidence: 99%

Application of Fragment-Based Drug Discovery to Versatile Targets

2020

Front. Mol. Biosci.

134

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Fragment-based drug discovery (FBDD) is a powerful method to develop potent smallmolecule compounds starting from fragments binding weakly to targets. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery. Many potent compounds/inhibitors of diverse targets have been developed using this approach. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. This review elucidates fragment libraries, methods utilized in fragment identification/confirmation, strategies applied in growing the identified fragments into drug-like lead compounds, and applications of FBDD to different targets. As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.

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“…The majority of CSF1R inhibitors also exhibit activity against these family members (as well as other kinases) and the converse is true, i.e., class III RTK inhibitors such as masitinib and sunitinib also inhibit CSF1R (Uitdehaag et al, 2011;Gandin et al, 2015). More recently, fragment-based drug design has been leveraged to identify novel starting points for CSF1R inhibition (Machiraju et al, 2019), presumably to better optimize selectivity and brain penetration.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Benn¹,

Dawson

2020

Front. Aging Neurosci.

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Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity.

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Identification, synthesis and evaluation of CSF1R inhibitors using fragment based drug design

Cited by 9 publications

References 45 publications

Overexpression of macrophage-colony stimulating factor-1 receptor as a prognostic factor for survival in cancer

Overexpression of macrophage-colony stimulating factor-1 receptor as a prognostic factor for survival in cancer

Application of Fragment-Based Drug Discovery to Versatile Targets

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

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