Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML

Carofiglio, Francesca; Lopalco, Antonio; Lopedota, Angela; Cutrignelli, Annalisa; Nicolotti, Orazio; Denora, Nunzio; Stefanachi, Angela; Leonetti, Francesco

doi:10.3390/ijms21124469

Cited by 22 publications

(12 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The breakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK that is an underlying cause of CML [ 21 ]. In 2001, the Bcr-Abl inhibitor Imatinib was used as first-line therapy for the treatment of CML [ 18 ].…”

Section: Indole/azaindole/oxindole-based Approved Atp-competitive Kin...mentioning

confidence: 99%

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Zhang

Gao

et al. 2023

Molecules

View full text Add to dashboard Cite

Kinases are among the most important families of biomolecules and play an essential role in the regulation of cell proliferation, apoptosis, metabolism, and other critical physiological processes. The dysregulation and gene mutation of kinases are linked to the occurrence and development of various human diseases, especially cancer. As a result, a growing number of small-molecule drugs based on kinase targets are being successfully developed and approved for the treatment of many diseases. The indole/azaindole/oxindole moieties are important key pharmacophores of many bioactive compounds and are generally used as excellent scaffolds for drug discovery in medicinal chemistry. To date, 30 ATP-competitive kinase inhibitors bearing the indole/azaindole/oxindole scaffold have been approved for the treatment of diseases. Herein, we summarize their research and development (R&D) process and describe their binding models to the ATP-binding sites of the target kinases. Moreover, we discuss the significant role of the indole/azaindole/oxindole skeletons in the interaction of their parent drug and target kinases, providing new medicinal chemistry inspiration and ideas for the subsequent development and optimization of kinase inhibitors.

show abstract

Section: Indole/azaindole/oxindole-based Approved Atp-competitive Kin...mentioning

confidence: 99%

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Zhang

Gao

et al. 2023

Molecules

View full text Add to dashboard Cite

show abstract

“…In the long term, one third of newly diagnosed children with CML-CP discontinued imatinib. Reasons for discontinuation were intolerance, resistance and lack of compliance [4][5][6]. Two second-generation TKIs, dasatinib and nilotinib, were developed as second line treatment in this setting and were approved in the frontline setting as well, also in children.…”

Section: Prognosis and Side Effectsmentioning

confidence: 99%

“…Overall, patients and their families should be encouraged to envision a normal family life, albeit under circumstances of strict disease control and pregnancy planning for female patients. Experience with imatinib and, to a lesser extent, with nilotinib and dasatinib constitutes the body of evidence on possible outcomes of the embryo after exposure during pregnancy [4].…”

Section: Reproductive Capacitymentioning

confidence: 99%

Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors

Moschovi

Kelaïdi

2021

IJMS

View full text Add to dashboard Cite

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. The goal of therapy in children and adolescents is normal life expectancy, without compromising normal growth and development and potential for achievement of milestones in adult life. The perspective of cure is also reflected in the goal of treatment-free remission, with its surrogate markers, such as deep molecular response, also becoming the new endpoints of therapy efficacy in children and adolescents. Chronic myeloid leukemia was a fatal disease to children and adolescents in the past. Following the treatment paradigm of imatinib, it became a chronic disease with the potential of complete remission and even cure without the long-term hazards of allogeneic hematopoietic cell transplantation. The diagnosis and treatment of CML affect a child’s trajectory through life and important physiological events like development and procreation.

show abstract

“…Recently, tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib have been approved for the treatment of chronic myeloid leukaemia in children, even though the studies that were concerned with efficacy and safety toward this population are still awaiting defined and more accurate data [ 17 , 18 , 19 ]. In this scenario, here, Carofiglio and colleagues [ 20 ] published a review article pointing out the importance of prospectively validating data extrapolated from adult studies to set a standard therapeutic management for paediatric chronic myeloid leukaemia by employing appropriate formulations on the basis of paediatric clinical trials, which allow a careful monitoring of tyrosine kinase inhibitor-induced adverse effects, especially in growing children exposed to long-term therapy. Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukaemia are more significant obstacles that require further clinical investigations.…”

Section: Articles In This Special Issuementioning

confidence: 99%

Paediatric Formulation: Design and Development

Lopalco

Denora

2020

IJMS

Self Cite

View full text Add to dashboard Cite

The development of medicines designed for children can be challenging since this distinct patient population requires specific needs. A formulation designed for paediatric patients must consider the following aspects: patient population variability; dose flexibility; route of administration; patient compliance; drug and excipient tolerability. The purpose of this Special Issue entitled “Paediatric Formulation: Design and Development” is to provide an update on both state-of-the-art methodology and operational challenges in the design and development of paediatric formulations. It aims at re-evaluating what is needed for more progress in the design and development of age-appropriate treatments for paediatric diseases, focusing on: formulation development; drug delivery design; efficacy, safety, and tolerability of drugs and excipients. This editorial, briefly, summarizes the objects of nine original research and review papers published in this Special Issue.

show abstract

Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML

Cited by 22 publications

References 93 publications

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors

Paediatric Formulation: Design and Development

Contact Info

Product

Resources

About