Inherent formulation issues of kinase inhibitors

Herbrink, Maikel; Schellens, Jan H.M.; Beijnen, Jos H.; Nuijen, Bastiaan

doi:10.1016/j.jconrel.2016.08.036

Cited by 20 publications

(14 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Special attention was paid to the aspecto fh igh selectivity with respectt ok inases in general as well as within the CDK family,i np articular high CDK9 selectivity.S uch CDK9 selectivity was anticipated as being crucial for the differentiation of ap otentialc andidate from cell-cycle-addressing selectiveC DK inhibitors (like the CDK4/6i nhibitor palbociclib [6] )a nd from pan-CDK inhibitors (like dinaciclib [7] or roniciclib [8] ), because adifferentiated activity and tolerability profile can be expected. Furthermore, favorable physicochemical and DMPK properties, which have been key hurdles in many kinasei nhibitor projects, [9] were of high importance.…”

Section: Resultsmentioning

confidence: 99%

Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

et al. 2017

View full text Add to dashboard Cite

Selective inhibition of exclusively transcription‐regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY‐958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“… 22 The assigned BCS class data are taken from the FDA clinical pharmacology, biopharmaceutics review documents and the published reviews. 23 , 24 The various BCS classes assigned to different TKIs are represented in Table 1 . The increase in Bioavailability of BCS class II drugs can be achieved by enhancing the dissolution.…”

Section: Physicochemical Factorsmentioning

confidence: 99%

Solid Lipid Nanoparticles for Efficient Oral Delivery of Tyrosine Kinase Inhibitors: A Nano Targeted Cancer Drug Delivery

Satapathy

Patro

2021

Adv Pharm Bull

View full text Add to dashboard Cite

Tyrosine kinase inhibitors (TKIs) are used as targeted therapy for cancer by inhibiting the signaling pathway and tumor growth. Many TKIs got approved by FDA in recent times for the treatment of cancer by oral route. However, the TKIs have formulation challenges leading to compromised bioavailability which can cause a weak therapeutic response. The cancer nanotherapeutics using nanocarriers based drug delivery has emerged as an advanced tool to provide a solution to formulation challenges and a better cancer therapy by overcoming the limitations in conventional cancer therapy. This review describes the various formulation issues of anticancer drugs with a special reference to TKIs, as well as the capability of solid lipid nanoparticles for an efficient nano targeted cancer drug delivery.

show abstract

“…Researchers should familiarize themselves with these off-target effects and use the lowest effective concentration of inhibitor to disfavor weaker binding interactions. Furthermore, many kinase inhibitors are poorly soluble in aqueous buffers, necessitating formulation for experiments in vivo or pretreatment for experiments in vitro (Eckstein et al, 2014;Herbrink, Schellens, Beijnen, & Nuijen, 2016). A final consideration when working with ATP-mimetic inhibitors is that these inhibitors typically bind and may even induce the active conformation of the kinase.…”

Section: Of 32mentioning

confidence: 99%

Immunopharmacology and Quantitative Analysis of Tyrosine Kinase Signaling

2020

View full text Add to dashboard Cite

In this article we describe the use of pharmacological and genetic tools coupled with immunoblotting (Western blotting) and targeted mass spectrometry to quantify immune signaling and cell activation mediated by tyrosine kinases. Transfer of the ATP γ phosphate to a protein tyrosine residue activates signaling cascades regulating the differentiation, survival, and effector functions of all cells, with unique roles in immune antigen receptor, polarization, and other signaling pathways. Defining the substrates and scaffolding interactions of tyrosine kinases is critical for revealing and therapeutically manipulating mechanisms of immune regulation. Quantitative analysis of the amplitude and kinetics of these effects is becoming ever more accessible experimentally and increasingly important for predicting complex downstream effects of therapeutics and for building computational models. Secondarily, quantitative analysis is increasingly expected by reviewers and journal editors, and statistical analysis of biological replicates can bolster claims of experimental rigor and reproducibility. Here we outline methods for perturbing tyrosine kinase activity in cells and quantifying protein phosphorylation in lysates and immunoprecipitates. The immunoblotting techniques are a guide to probing the dynamics of protein abundance, protein-protein interactions, and changes in post-translational modification. Immunoprecipitated protein complexes can also be subjected to targeted mass spectrometry to probe novel sites of modification and multiply modified or understudied proteins that cannot be resolved by immunoblotting. Together, these protocols form a framework for identifying the unique contributions of tyrosine kinases to cell activation and elucidating the mechanisms governing immune cell regulation in health and disease.

show abstract

Inherent formulation issues of kinase inhibitors

Cited by 20 publications

References 97 publications

Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

Solid Lipid Nanoparticles for Efficient Oral Delivery of Tyrosine Kinase Inhibitors: A Nano Targeted Cancer Drug Delivery

Immunopharmacology and Quantitative Analysis of Tyrosine Kinase Signaling

Contact Info

Product

Resources

About