6-Bromo-2-methyl-imidazo[1,2-a]pyridine-8-carbonitrile cas 2092561-23-2

· CAS Number: 2092561-23-2
· Generic Name (INN): Zipalertinib
· Development Code: CLN-081 (developed by company Cullinan Oncology)
· Chemical Name: Usually a complex IUPAC name, used in scientific literature and patents.
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Drug Classification and Mechanism of Action
Zipalertinib belongs to a class of targeted anti-cancer drugs known as tyrosine kinase inhibitors (TKIs).
· Target: Its main target is the epidermal growth factor receptor (EGFR).
· Mechanism of action:
1. Background: In some patients with non-small cell lung cancer (NSCLC), the EGFR gene undergoes specific mutations (such as exon 19 deletion or L858R point mutation, known as "classic mutations"), which leads to the continuous growth of cancer cells. First and second-generation EGFR TKIs (such as gefitinib, erlotinib, afatinib) are effective against these mutations, but patients eventually develop resistance.
2. Main resistance mutations: Approximately 50%-60% of resistance cases are due to the emergence of the T790M mutation.
3. Third-generation TKIs: Third-generation EGFR TKIs like osimertinib have been developed, which can effectively combat mutations containing the T790M.
4. The uniqueness of Zipalertinib: Zipalertinib is classified as an EGFR inhibitor and has high selectivity for EGFR exon 20 insertion (Exon 20 Insertion, ex20ins) mutations.
The EGFR ex20ins mutation is a relatively rare but challenging type of mutation, and it is insensitive to early EGFR TKIs (including some third-generation TKIs). The design of Zipalertinib is precisely to fill this treatment gap.
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Main Characteristics and Clinical Significance
1. Targeting refractory sites: The main clinical value of Zipalertinib lies in treating patients with advanced or metastatic non-small cell lung cancer (NSCLC) who carry the EGFR ex20ins mutation. This is a patient group with limited treatment options and poor prognosis in the past.
2. High selectivity: Compared with other similar drugs (such as Mobocertinib/TAK-788), Zipalertinib shows highly efficient inhibition of EGFR ex20ins mutations in preclinical and clinical studies, while its inhibitory activity on wild-type EGFR is relatively low.
3. Safety advantages: Due to its relatively weak inhibition of wild-type EGFR, it is theoretically possible to reduce typical side effects associated with wild-type EGFR inhibition, such as severe rashes and diarrhea, thereby potentially having better tolerability and safety. This has been preliminarily confirmed in the published clinical data.
4. Broad-spectrum activity: In addition to being effective against ex20ins mutations, the study also indicates that it has certain inhibitory activity against classic EGFR mutations (such as 19del, L858R) and drug-resistant mutations containing T790M, but its development focus is on ex20ins.
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Research and Development Status
· Zipalertinib has completed the crucial Phase II clinical trial and has demonstrated encouraging efficacy and good safety.
· Based on these positive data, the company developing it, Cullinan Oncology, submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) in 2023 and it is currently under review.
· It is expected to become another targeted treatment option for EGFR ex20ins mutation NSCLC after mabossitib and amivantamab, providing patients with additional treatment choices.
Summary

In summary, CAS 2092561-23-2 (Zipalertinib/CLN-081) is a highly selective, novel oral targeted anti-cancer drug specifically targeting EGFR exon 20 insertion mutations. It demonstrates great potential in addressing a difficult mutation subtype in non-small cell lung cancer and has attracted significant attention due to its potentially superior safety profile. It is a very important investigational drug in the current field of precision medicine for lung cancer.