Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered by a Fragment Optimization Approach
Debasmita Saha1, Katie Rose Ryan2, Naga Rajiv Lakkaniga1,3
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
Abstract:
A fragment-based drug-discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ∼2 % of non-small-cell lung cancers. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA-driven matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found to be active on RET in a biochemical assay, but reduced cell viability in non-RET-driven cell lines (EC50 =1 and 3 μM, respectively). To increase selectivity for RET, the pyrazoloadenine was modeled in the RET active site, and two domains were identified that were probed with pyrazoloadenine fragment derivatives to improve RET affinity. Scaffolds at each domain were merged to generate a novel lead compound, 8 p, which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC50 =5.92 μM, LC-2/ad EC50 =0.016 μM, RET IC50 =0.000326 μM).
Insights
Researchers discovered a new drug candidate, 8p, using fragment-based drug discovery to target the RET oncoprotein. This molecule shows improved selectivity and activity against RET-driven non-small cell lung cancer cells.
Area of Science:
- Oncology
- Medicinal Chemistry
- Drug Discovery
Background:
- The RET (REarranged during Transfection) oncoprotein drives approximately 2% of non-small cell lung cancers.
- Targeting oncogenic drivers like RET is a key strategy in precision oncology.
Purpose of the Study:
- To identify novel small molecules that selectively inhibit the RET oncoprotein using a fragment-based drug discovery approach.
- To develop a lead compound with improved potency and selectivity against RET-driven cancer cells.
Main Methods:
- Screening of a pyrazoloadenine fragment library against RET kinase and relevant cell lines (LC-2/ad, KM-12, A549).
- Structure-based drug design involving modeling the pyrazoloadenine fragment in the RET active site.
- Synthesis and evaluation of pyrazoloadenine derivatives and merged scaffolds to optimize RET affinity and selectivity.
Main Results:
- An initial pyrazoloadenine fragment showed activity against RET but lacked selectivity.
- Modeling identified key domains for modification, leading to improved RET affinity.
- The novel lead compound, 8p, demonstrated significantly enhanced activity and selectivity for RET (IC50 = 0.000326 μM) compared to non-RET-driven cells.
Conclusions:
- Fragment-based drug discovery is effective for identifying selective inhibitors of oncogenic proteins like RET.
- The lead compound 8p represents a promising candidate for further development in treating RET-driven non-small cell lung cancer.
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