A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

Uitdehaag, Joost C.M.; Verkaar, Folkert; Alwan, Husam; Man, Jos de; Buijsman, Rogier C.; Zaman, Guido J.R.

doi:10.1111/j.1476-5381.2012.01859.x

Cited by 97 publications

(97 citation statements)

References 168 publications

(281 reference statements)

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“…Seventy-eight AYA patients were evaluated for FLT3 , with mutations identified in 28%: 17 (22%) patients had internal tandem duplication 19 , 8 (10%) had D835 point mutation and 3 (4%) had both FLT3 -ITD and D835 abnormalities. An NPM1 mutation was identified in 6 of 23 evaluable patients (26%).…”

Section: Resultsmentioning

confidence: 99%

Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) With Acute Myeloid Leukemia (AML)

Pemmaraju

Kantarjian

Ravandi

et al. 2016

Clinical Lymphoma Myeloma and Leukemia

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Background Little is known about outcomes of AML in adolescents and young adults (AYA). The purpose of this study is to determine the characteristics and outcomes of AYA AML patients in comparison to older adult patients with AML. Patients and Methods We retrospectively analyzed all AML patients treated at our institution from 1965 to 2009 aged 16 to 29 years. Results Among 3,922 adult AML patients treated during this period, 432 (11%) were identified as AYA. Median age was 23 years (range 16-29 years); 73 (17%) patients had Core Binding Factor (CBF)-AML [inv (16), t(8:21)] and 51 (12%) acute promyelocytic leukemia. Complete remission (CR) rates were 93% for CBF AML, 78% for APL, 77% with diploid karyotype and 68% for other AML. Univariate analysis demonstrated higher rates of complete remission (CR), CR duration, and overall survival (OS) in the AYA group compared to older patients. On multivariate analysis, AYA age group was independently associated with improved CR rate and CR duration, with a trend for longer OS (p-value=0.085). Conclusion Outcome of AYA AML patients is overall better than for older adults with AML. Despite improvements in treatments and outcomes over time, there is still need for improvement in AYA with AML particularly for those with AML other than CBF and APL.

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Section: Resultsmentioning

confidence: 99%

Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) With Acute Myeloid Leukemia (AML)

Pemmaraju

Kantarjian

Ravandi

et al. 2016

Clinical Lymphoma Myeloma and Leukemia

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“…Neflamapimod (previously code‐named VX‐745)18 is a highly selective oral small molecule inhibitor of p38 α that after oral administration in animals achieves brain concentrations that are ~twofold higher than in blood 16, 19, 20. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with rheumatoid arthritis, neflamapimod was repositioned as a CNS therapeutic 16.…”

Section: Introductionmentioning

confidence: 99%

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

Scheltens

Prins

Lammertsma

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters.MethodsSixteen patients with early AD received a highly selective p38α inhibitor (neflamapimod) for 84 days (12 weeks). To obtain a broad range of plasma drug exposures, subjects randomized to receive either 40 mg (n = 9) or 125 mg (n = 7) twice daily. Dynamic, 11C‐PiB positron emission scans were performed at baseline and at Day 84 and quantitatively analyzed by reference parametric mapping. Episodic memory assessed as Wechsler Memory Scale (WMS) immediate and delayed recall composites.ResultIn the 11C‐PiB analyses there were no main group level effects, though in the prespecified responder analysis (>7% reduction in 11C‐PiB signal) there were three responders in the 40 mg, and one in the 125 mg group. There were statistically significant increases from baseline in mean WMS immediate recall score and WMS delayed recall at both day 28 (P = 0.03 and P = 0.001) and day 84 (P = 0.001 and P < 0.001). Individual subject plasma drug concentration profiles were significantly positively correlated with the change in combined WMS immediate and delayed recall (P < 0.0001, r 2= 0.70). Within‐subject effect size was 0.59 for immediate recall and 0.67 for delayed recall.InterpretationSelective p38α inhibition in patients with early AD may improve episodic memory and potentially impact β‐amyloid production. These preliminary clinical findings support conduct of a longer duration placebo‐controlled study, particularly to confirm the effects on episodic memory function.

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“…2-4 The association of many NRTKs with cancer and inflammatory disease has led to large drug discovery efforts, resulting in the development of 24 FDA-approved small molecule NRTK inhibitors since 2001. 5 However, despite their established clinical importance, approved inhibitors target only a small subset of NRTKs (5 out of 32). A major factor impeding development of kinase inhibitors is the difficulty in producing compounds that are highly specific, and several promising kinase inhibitors have failed clinical trials due to unanticipated off-target effects.…”

Section: Introductionmentioning

confidence: 99%

KINATEST-ID: A Pipeline To Develop Phosphorylation-Dependent Terbium Sensitizing Kinase Assays

et al. 2015

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Non-receptor protein tyrosine kinases (NRTKs) are essential for cellular homeostasis, and thus are a major focus of current drug discovery efforts. Peptide substrates that can enhance lanthanide ion luminescence upon tyrosine phosphorylation enable rapid, sensitive screening of kinase activity, however design of suitable substrates that can distinguish between tyrosine kinase families is a huge challenge. Despite their different substrate preferences, many NRTKs are structurally similar even between families. Furthermore, the development of lanthanide-based kinase assays is hampered by incomplete understanding of how to integrate sequence selectivity with metal ion binding, necessitating laborious iterative substrate optimization. We used curated proteomic data from endogenous kinase substrates and known Tb3+-binding sequences to build a generalizable in silico pipeline with tools to generate, screen, align and select potential phosphorylation-dependent Tb3+-sensitizing substrates that are most likely to be kinase specific. We demonstrated the approach by developing several substrates that are selective within kinase families and amenable to HTS applications. Overall, this strategy represents a pipeline for developing efficient and specific assays for virtually any tyrosine kinase that use high throughput screening-compatible lanthanide-based detection. The tools provided in the pipeline also have the potential to be adapted to identify peptides for other purposes, including other enzyme assays or protein binding ligands.

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A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

Cited by 97 publications

References 168 publications

Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) With Acute Myeloid Leukemia (AML)

Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) With Acute Myeloid Leukemia (AML)

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

KINATEST-ID: A Pipeline To Develop Phosphorylation-Dependent Terbium Sensitizing Kinase Assays

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