TY - JOUR
T1 - Targeting the RET tyrosine kinase in neuroblastoma
T2 - A review and application of a novel selective drug design strategy
AU - Steen, Erica
AU - Basilaia, Mariam
AU - Kim, William
AU - Getz, Taelor
AU - Gustafson, Jeffrey L.
AU - Zage, Peter E.
N1 - Publisher Copyright:
© 2023
PY - 2023/10
Y1 - 2023/10
N2 - The RET (REarranged during Transfection) gene, which encodes for a transmembrane receptor tyrosine kinase, is an established oncogene associated with the etiology and progression of multiple types of cancer. Oncogenic RET mutations and rearrangements resulting in gene fusions have been identified in many adult cancers, including medullary and papillary thyroid cancers, lung adenocarcinomas, colon and breast cancers, and many others. While genetic RET aberrations are much less common in pediatric solid tumors, increased RET expression has been shown to be associated with poor prognosis in children with solid tumors such as neuroblastoma, prompting an interest in RET inhibition as a form of therapy for these children. A number of kinase inhibitors currently in use for patients with cancer have RET inhibitory activity, but these inhibitors also display activity against other kinases, resulting in unwanted side effects and limiting their safety and efficacy. Recent efforts have been focused on developing more specific RET inhibitors, but due to high levels of conservation between kinase binding pockets, specificity remains a drug design challenge. Here, we review the background of RET as a potential therapeutic target in neuroblastoma tumors and the results of recent preclinical studies and clinical trials evaluating the safety and efficacy of RET inhibition in adults and children. We also present a novel approach to drug discovery leveraging the chemical phenomenon of atropisomerism to develop specific RET inhibitors and present preliminary data demonstrating the efficacy of a novel RET inhibitor against neuroblastoma tumor cells.
AB - The RET (REarranged during Transfection) gene, which encodes for a transmembrane receptor tyrosine kinase, is an established oncogene associated with the etiology and progression of multiple types of cancer. Oncogenic RET mutations and rearrangements resulting in gene fusions have been identified in many adult cancers, including medullary and papillary thyroid cancers, lung adenocarcinomas, colon and breast cancers, and many others. While genetic RET aberrations are much less common in pediatric solid tumors, increased RET expression has been shown to be associated with poor prognosis in children with solid tumors such as neuroblastoma, prompting an interest in RET inhibition as a form of therapy for these children. A number of kinase inhibitors currently in use for patients with cancer have RET inhibitory activity, but these inhibitors also display activity against other kinases, resulting in unwanted side effects and limiting their safety and efficacy. Recent efforts have been focused on developing more specific RET inhibitors, but due to high levels of conservation between kinase binding pockets, specificity remains a drug design challenge. Here, we review the background of RET as a potential therapeutic target in neuroblastoma tumors and the results of recent preclinical studies and clinical trials evaluating the safety and efficacy of RET inhibition in adults and children. We also present a novel approach to drug discovery leveraging the chemical phenomenon of atropisomerism to develop specific RET inhibitors and present preliminary data demonstrating the efficacy of a novel RET inhibitor against neuroblastoma tumor cells.
KW - Atropisomerism
KW - Getretinib
KW - Neuroblastoma
KW - RET
KW - Proto-Oncogene Proteins c-ret/genetics
KW - Humans
KW - Thyroid Neoplasms/drug therapy
KW - Neuroblastoma/drug therapy
KW - Lung Neoplasms/drug therapy
KW - Drug Design
KW - Adult
KW - Protein Kinase Inhibitors/pharmacology
KW - Protein-Tyrosine Kinases
KW - Child
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U2 - 10.1016/j.bcp.2023.115751
DO - 10.1016/j.bcp.2023.115751
M3 - Review article
C2 - 37595672
AN - SCOPUS:85169321595
SN - 0006-2952
VL - 216
SP - 115751
JO - Biochemical pharmacology
JF - Biochemical pharmacology
M1 - 115751
ER -