Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position

Jordan, Allan M.; Begum, Habiba; Fairweather, Emma; Fritzl, Samantha J R; Goldberg, Kristin; Hamilton, Niall M.; Lyons, Amanda; March, H. Nikki; Newton, Rebecca; Small, Helen; Vishwanath, Shilpa; Waddell, Ian D.; Waszkowycz, Bohdan; Watson, Amanda J.; Ogilvie, Donald

doi:10.1016/j.bmcl.2016.03.100

Cited by 8 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The key to increased selectivity compared to vandetanib was a change in substituents around the phenyl ring, which also led to improved metabolic and pharmacokinetic features . This family was further elaborated in a more recent work, where the authors identified compounds with improved cellular selectivity (Jordan et al 2016).…”

Section: Next Generation Of Ret Targeted Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

View full text Add to dashboard Cite

The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

show abstract

Section: Next Generation Of Ret Targeted Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…A collection of 42 anilinoquinazoline derivatives as RET kinase antagonists were taken for the study . Converted pIC 50 values (−log IC 50 ) from the reported IC 50 values (μM) of the compounds shows the log span of 3.7 which is satisfactory to perform a 3D‐QSAR study .…”

Section: Methodsmentioning

confidence: 97%

“…Recently FDA and EMA have approved vandetanib, cabozantinib, sorafenib, and lenvatinib for the treatment of MTC. But, these inhibitors are non‐selective to RET and possess elevated efficacy against some other protein kinases . These drugs are also ineffective inhibitors against the gatekeeper mutants V804M and V804L .…”

Section: Introductionmentioning

confidence: 99%

Receptor‐guided 3D‐QSAR Study of Anilinoquinazolines as RET Receptor Tyrosine Kinase Antagonists

Bhujbal

Balasubramanian

Keretsu

et al. 2019

Bulletin Korean Chem Soc

View full text Add to dashboard Cite

A RET (Rearranged during transfection) kinase belongs to a receptor tyrosine kinase family. It plays a major role in development, maturation, survival, and maintenance of cells and tissues. Oncogenic activation of RET has been reported in numerous cancers. Thus, it is a significant therapeutic target for cancer. Present work covers docking and 3D-QSAR techniques executed on anilinoquinazoline derivatives as RET kinase antagonists. Docking study recognized important active site amino acid residues like Leu730, Gly731, Gly733, Glu734, Ala807, Gly810, Ser811, and Asp874 which inhibits the RET kinase. In 3D-QSAR technique, receptor-guided CoMFA (q 2 = 0.723, NOC = 5, r 2 = 0.980) as well as CoMSIA (q 2 = 0.767, NOC = 6, r 2 = 0.967) models were produced. The stabilities of these models were evaluated using diverse validation techniques. Contour maps showed that steric and hydrogen bond donor substitutions are favored at R 1 and R 2 positions whereas positive and negative substitutions are favored at the R 1 position to enhance the potency. In addition, the substitution of H-bond accepting group to the region which is close to both phenyl and piperazine is favored. Hence, the outcome of this study could be beneficial to design more potent inhibitors for RET kinase.

show abstract

“…Within the organizations collaborating in this work and in those who have been able to exploit the data in trial form in universities and not for profit organizations, the knowledge has contributed to solving a number of drug hunting project problems leading to several publications . [40][41][42] We have also shown examples of transformations that run counter to established wisdom. These may be useful tools to extricate a drug hunting team from a tight optimization corner and more generally to provide opportunities to enhance our understanding of the general SAR of the system being studied.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA)

Krämer

Ting

Zheng³

et al. 2017

J. Med. Chem.

View full text Add to dashboard Cite

The first large scale analysis of in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) data shared across multiple major pharma has been performed. Using advanced matched molecular pair analysis (MMPA), we combined data from three pharmaceutical companies and generated ADMET rules, avoiding the need to disclose the full chemical structures. On top of the very large exchange of knowledge, all companies involved synergistically gained approximately 20% more rules from the shared transformations. There is good quantitative agreement between the rules based on shared data compared to both individual companies' rules and rules published in the literature. Known correlations between log D, solubility, in vitro clearance, and plasma protein binding also hold in transformation space, but there are also interesting exceptions. Data pools such as this allow focusing on particular functional groups and characterizing their ADMET profile. Finally the role of a corpus of robustly tested medicinal chemistry knowledge in the training of medicinal chemistry is discussed.

show abstract

Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position

Abstract: Graphical abstract

Cited by 8 publications

References 21 publications

Novel targeted therapeutics for MEN2

Novel targeted therapeutics for MEN2

Receptor‐guided 3D‐QSAR Study of Anilinoquinazolines as RET Receptor Tyrosine Kinase Antagonists

Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA)

Contact Info

Product

Resources

About