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Updated: May 3, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Structure-based optimization of tyrosine kinase inhibitor CLM3. Design, synthesis, functional evaluation, and
Stefania Sartini1, Vito Coviello, Agostino Bruno
1Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
Abstract:
Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RET(V804L), which still lacks effective inhibitors.
Insights
New pyrazolo[3,4-d]pyrimidine derivatives show potent inhibition of VEGFR2 and RET kinases. These compounds demonstrate improved antiproliferative effects against medullary thyroid cancer, including activity against the challenging RET(V804L) mutation.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Thyroid carcinoma development is linked to receptor tyrosine kinases (RTKs), specifically VEGFR2 and RET.
- Inhibition of these RTKs is a key therapeutic strategy for thyroid cancers.
- Existing inhibitors often struggle with specific mutations, such as RET(V804L).
Purpose of the Study:
- To synthesize and functionally evaluate novel 4-substituted pyrazolo[3,4-d]pyrimidine derivatives.
- To optimize previously developed inhibitors for enhanced activity against VEGFR2 and RET.
- To identify compounds effective against drug-resistant mutations like RET(V804L).
Main Methods:
- Structure-based optimization of the CLM3 inhibitor scaffold.
- Synthesis of three series of pyrazolo[3,4-d]pyrimidine derivatives (8a-g, 9a-g, 10a-g).
- In vitro evaluation of inhibitory profiles against VEGFR2 and RET kinases.
- Assessment of antiproliferative efficacy against the TT medullary thyroid cancer cell line.
Main Results:
- Novel derivatives demonstrated improved inhibitory activity against both VEGFR2 and RET targets compared to the lead compound.
- Compounds exhibited enhanced antiproliferative effects on the TT medullary thyroid cancer cell line.
- Compounds 8b, 9c, and 10c successfully inhibited the kinase activity of the mutant RET(V804L).
Conclusions:
- The novel pyrazolo[3,4-d]pyrimidine derivatives represent promising therapeutic agents for thyroid carcinomas.
- These compounds offer improved efficacy and a broader inhibitory profile, including against resistant RET mutations.
- Further development of these inhibitors could lead to more effective treatments for medullary thyroid cancer.
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