Breaking: Class 1 Innovative Small-molecule BTK-PROTAC Antineoplastic Drugs Approved

On January 26th, the application for the clinical trial of HSK29116 powder declared by Sichuan Haisco Pharmaceutical Co., Ltd. was accepted by the State Food and Drug Administration.

HSK29116 is an oral PROTAC small molecule antineoplastic drug, which can selectively block the activity of BTK kinase and interfere with B cell development by regulating signal pathways, thus controlling the progression of various B cell malignant tumors. On the one hand, HSK29116 can directly inhibit the activity of BTK by specifically binding to BTK; on the other hand, it can induce BTK ubiquitin labeling and degrade it through the proteasome pathway, thus blocking the transmission of BCR signal pathway, inhibiting the growth and proliferation of B-cell lymphoma cells, and playing a dual anti-tumor effect.

At present, small molecule inhibitors of BTK have been successfully used in the treatment of B-cell lymphoma. But the existing listed BTK inhibitors mainly produce enzyme inhibition by forming a covalent bond with the cysteine residues of the BTK active site, which has great side effects. Moreover, covalent binding is easy to produce drug-resistant mutations, which becomes a major problem in clinical treatment.

According to the announcement, HSK29116 not only has better efficacy against wild-type BTK, but also can overcome the problem of drug resistance mutation. If it is successfully listed, it will bring more clinical benefits and better therapeutic drugs for patients with B-cell malignant tumors.

Up to now, no products with the same target and mechanism as HSK29116 have entered clinical trials, and HSK29116 is expected to become a first-in-class drug.

PROTAC is a hot topic in medical research in recent years. Its full name is Proteolysis-Targeting Chimeras whose structure looks like a dumbbell that connects “ligands of interest proteins” to “E3 ubiquitin ligase-recruiting ligands” through a “linker“. E3 ubiquitin ligase can mark a small protein called ubiquitin as defective or damaged by attaching it to the target protein. After that, the cell’s protein shredder (that is, proteasome) will degrade the labeled target protein.

Compared with traditional protein inhibitors, PROTAC-based protein degradants have unique advantages. Among them, one of the biggest advantages is the ability to change the target from “undruggable” to “druggable”. In addition, PROTAC is expected to solve the problem of drug resistance of traditional protein inhibitors.