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Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent
Marialuisa Moccia1, Brendan Frett2,3, Lingtian Zhang2
1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy.
Abstract:
RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key in vivo metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed a selective inhibitory profile and an inhibitory concentration 50 (IC50) of <0.003 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumors induced by RET/C634Y-transformed cells, while it weakened, but did not abrogate, formation of tumors induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers.
Insights
A new drug candidate, NPA101.3, effectively targets RET and VEGFR2, inhibiting cancer cell growth and tumor formation in preclinical models. This compound overcomes a key metabolic issue, making it a promising therapy for RET-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RET receptor tyrosine kinase is a known driver oncogene in various human cancers.
- Previous drug candidate Pz-1 targets both RET and VEGFR2 but has a less active metabolite.
- This metabolite arises from demethylation, posing a challenge for sustained therapeutic efficacy.
Purpose of the Study:
- To identify a novel RET and VEGFR2 inhibitor resistant to demethylation.
- To evaluate the preclinical efficacy of the new compound, NPA101.3, in RET-driven cancer models.
Main Methods:
- Utilized bioisosteric substitution to design NPA101.3, a molecule lacking the demethylation liability.
- Assessed the inhibitory activity (IC50) of NPA101.3 against RET and VEGFR2.
- Evaluated the compound's effect on RET oncoprotein and VEGFR2 phosphorylation, cell proliferation, and tumor formation in vivo.
Main Results:
- NPA101.3 demonstrated potent and selective inhibition of RET and VEGFR2 with an IC50 <0.003 μM.
- The compound effectively inhibited RET oncoprotein and VEGFR2 phosphorylation and reduced proliferation of RET-transformed cells.
- Oral administration of NPA101.3 completely prevented tumor formation in a RET/C634Y-driven model.
Conclusions:
- NPA101.3 is a novel inhibitor with balanced, synchronous inhibition of RET and VEGFR2.
- Its resistance to demethylation and potent preclinical efficacy position it as a strong clinical candidate for RET-driven cancers.
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