Interpretation of the patented route of Ensartinib, a home-made APK inhibitor

Recently, China's Beda Pharmaceuticals and holding subsidiary Xcovery of the United States jointly developed a new oral second-generation powerful, highly selective ALC-TKI-Ensartinib (commodity name: Be mena ®) successfully obtained our country The Drug Administration (NMPA) has been approved for the treatment of patients with crazotinib or patients with ALK-positive localized advanced or metastasis non-small cell lung cancer who have been treated with crizotinib or are insatiable with crizotinib.
is also the first listed APK inhibitor with independent intellectual property rights in China.
, Ensartinib structured lung cancer has the highest incidence and mortality rate of malignant tumors worldwide, accounting for 11.6 per cent of new cancer cases and 18.4 per cent of tumor-related deaths worldwide.
according to the China Cancer Center, the number of new cases of lung cancer in China reached 787,000 in 2015 and the number of deaths reached 631,000, which poses a great threat to the health of our people.
lung cancer, 85% are non-small cell lung cancer (NSCLC), while the current five-year survival rate of non-small cell lung cancer (NSCLC) is only 10%-15%, the quality of treatment obviously needs to be further improved.
APK as a transmerally-like tyrosine kinase, belonging to the insulin-subject super family.
about 3% to 7% of patients with non-small cell lung cancer (NSCLC) have ALC gene fusion.
now, ALK inhibitors have become a focus area for non-small cell lung cancer (NSCLC) targeted therapy after the skin growth factor inhibitor tyrosine kinase inhibitor (EGFR-TKI).
Ensartinib is a new APK inhibitor with a half-inhibitory concentration (IC50) of ALK tyrosine kinase at the molecular level;
at the cellular level, Ensartinib can effectively inhibit ALK phosphorylation and can inhibit out-of-cell regulatory protein kinase (ERK) and protein kinase B (PKB) downstream target, in tumor cells carrying different APK fusion proteins, including H312 Ensartinib has excellent anti-proliferation activity in lung cancer cell strains, H2228 lung cancer cell strains, SU-DHL-1 lymphoma cell strains, and SY5Y neuroblastoma cell strains, and inhibits more than 10 times as much as Crizotinib.
2 Ensartinib Patented Synthesis Process (WO2012048259A2) Currently, Ensartinib publishes only patented processes (WO2012048259A2).
As shown in Figure II, drug developers use hand alcohols 1 and clatter 2 as the initial raw material, under the action of NaH, a pro-nuclear replacement reaction is obtained by intermediate 3; 5 Then LiOH under the action of ester hydrolytic reaction, acidification obtained the compound 6, compound 6 under the action of the shrink agent and compound 7 alamide shrinkage to obtain the prebiotic compound 8, and finally, under the acidic action of TFA to take off the Boc protection base, you can get the target product Ensartinib.
the patented process, except for the first step of low yield, other steps have maintained a high yield.
with the development of technology, especially the improvement and popularization of molecular-level diagnostic technology, precision treatment or personalized drug use based on drug resistance mechanism is becoming more and more popular with doctors and patients.
and launch of a new broad-spectrum APK-TKI, providing doctors with more options for precision treatment.
Ensartinib, as china's first independently developed ALK inhibitor with independent intellectual property rights and a new molecular entity, has better efficacy and safety in clinical efficacy evaluation, clinical safety evaluation and benefit risk assessment data.
: 1. Pharmacology and Clinical Evaluation of Ensartinib Hydrochloride Capsule,2020; 2. World Patent: WO2012048259A2; 3. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,2018.