Progress: The development of a non-covalent BTK inhibitor (AS-1763) in clinical phase I

The full name of BTK is Bruton's tyrosine kinase.
It is a member of the TEC family of non-receptor tyrosine kinases in the cytoplasm.
Except for T cells and plasma cells, it is found in all hematopoietic cells.
Express
.
BTK is a key kinase in the BCR (B cell surface antigen receptor) signaling pathway.
It plays an important role in the growth, development, proliferation and differentiation of B cells.
Abnormal BTK may induce cancer or autoimmune diseases
.
At present, the incidence of lymphoma in China is about 6.
3 per 100,000, and there are about 90,000 new cases each year, with an annual growth rate of 5%-7%; autoimmune diseases such as rheumatoid arthritis and ankylosing spine The incidence of inflammation and psoriasis are between 0.
1% and 0.
3%.
It is estimated that by 2024, the number of the above three diseases will be 6.
120 million, 3.
971 million, and 6.
763 million respectively
.
The increase in the number of tumors and autoimmune diseases will bring about an increase in the demand for drugs
.
At present, the global sales scale of BTK inhibitors on the market has exceeded US$10 billion
.
Among them, the global sales scale of ibrutinib in 2020 will reach 9.
44 billion U.
S.
dollars (sales of 7.
37 billion U.
S.
dollars in the first three quarters of 2021), and it is predicted that the sales will reach 13.
6 billion U.
S.
dollars in 2026, which is an epic blockbuster product
.
Among the products launched after Ibrutinib, the sales scale of acatinib (2020.
3-2021.
3) is 520 million U.
S.
dollars; BeiGene's Zebutinib has sales of 41.
7 million U.
S.
dollars in 2020, and BeiGene's Zebu Tinib PK ibrutinib head-to-head in the United States, and a single positive drug cost more than 100 million US dollars; Nuocheng Jianhua’s obritinib was sold to Biogen, only for multiple sclerosis and overseas autoimmune indications , The down payment is as high as 125 million U.
S.
dollars; Gilead’s Tilarutinib was launched late, and its sales contribution is relatively small in the BTK market
.
Hengrui Medicine’s BTK inhibitor SHR-1459 is currently in Phase II clinical trials, and its overseas rights have also been transferred to TG Therapeutics.

.
There are still dozens of domestic companies still deploying in the BTK market, such as Huadong Medicine’s CX-1440 and Hangzhou Hezheng’s HA-Z-018
.
Bruton's tyrosine protein kinase (BTK) has been recognized as an effective drug target for the treatment of B-cell malignancies, but the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious problem
.
PROTAC is one of the possible solutions.
At present, BeiGene (BGB-16673) and Haisco (HSK-29116) are currently deploying BTK PROTAC in China and entering the clinical stage
.
According to the materials from BeiGene Research and Development Day, preclinical models show that BGB-16673 can overcome C481S resistance and is expected to solve the problem of patients' resistance to Zebutinib and other BTK inhibitors
.
Japan’s Carna Biosciences recently wrote an article on JMC’s Drug Annotation and reported that it has developed a new type of non-covalent inhibitor of pyrropyrimidine backbone, which is effective against both wild-type and C481S mutant BTK inhibitors
.
The article shows that AS-1763 has significant efficacy in in vivo xenogeneic tumor models and has entered phase 1 clinical trials
.
This article briefly introduces the discovery process of AS-1763
.
The first generation of covalent BTK inhibitors represented by ibrutinib has been considered a promising targeted therapy for patients with B-cell malignancies
.
However, drug resistance has become a serious problem
.
The resistance mechanism of the first generation of BTK inhibitors is mainly due to the substitution of the cysteine ​​residue at position 481 by a serine residue (C481S mutation), which prevents the covalent binding of the inhibitor and reduces the inhibitory activity
.
There are still highly unmet clinical needs for new treatments to overcome BTK C481s-mediated drug resistance, and non-covalent and reversible BTK inhibitors are currently very important choices
.
Currently, as shown in Figure 2, some non-covalent and reversible BTK inhibitors have been developed for tumor and autoimmunity, and have entered clinical trials
.
The indication for AS-1763(13f) is exactly the wild-type and C481S mutant B-cell malignancies in BTK
.
Initially molecular docking was carried out based on the protein of compound 6 and BTK (referring to the co-crystal of carna's previous triazine compound and BTK protein), and the interaction of N and H in the molecule was observed.
The two Ns marked by the arrow did not seem to contribute to the binding.
Therefore, the researchers cyclized at the aminotriazine site to obtain compound 7, which is the backbone molecule of pyrrolopyrimidine; compound 7 has good antiproliferative activity in OCI-Ly10, and the IC50 value for BTK[A] is 14 nM
.
Initially screened at R1 in Table1; when the pyridine fragment was introduced, both the inhibition of BTK[A] and OCI-Ly10 were greatly improved; this suggested that the hydrogen bond acceptor needs to be introduced in the solvent region; in the moderate "saturation" When the pyridine ring and the acetyl group are added, the cell viability of compound 12 is 4.
8 times higher than that of 11 (IC50 = 0.
71 nM for BTK[A] and 5 nM for OCI-Ly10)
.
However, the Caco-2 membrane permeability of compound 12 is very low
.
Table 2 mainly balances the problems of activity and permeability by changing the substituents on N in the solvent region; Carna mentioned that the introduction of oxetane, an important drug-like fragment, finally solved the problem of Caco-2, and They are based on the fact that oxetane mentioned in related reports in recent years can improve drug-like properties, including solubility and permeability
.
Medicinalization requires constant trial and error, and perhaps stagnates without trying out this fragment project
.
A kinase profile inhibition test was performed for compound 13f to verify the selectivity.
The purpose is to develop a compound that can inhibit wild-type and c481s mutant BTK
.
The cell viability test in the blue box in Figure 5 can indeed draw this conclusion, but it is strange that the IC50 of Ibrutinib for BTK[C481S] and the IC50 for OCI-Ly10 [BTK C481S] are quite different.

.
The in vitro ADMET data in Figure 5 shows that compound 13f also has no metabolic problems
.
In the end, Carna Biosciences of Japan discovered a class of pyrropyrimidine skeleton compounds through the strategy of skeleton transition, which is a selective and non-covalent BTK inhibitor
.
Compound 13f (AS -1763) has entered the first clinical phase, and domestic Yehui Pharmaceutical has obtained the license to develop and commercialize AS-1763 in Mainland China, Hong Kong, Macau and Taiwan
.
Columnist: Xingxinghu medicinal chemistry background, has been engaged in target research, patent analysis and breakthroughs, and improved new drugs; now focuses on the molecular design of innovative drugs; loves the pharmaceutical industry, and is willing to learn from each other, make progress, and witness innovative drugs The best times
.
References: 1, Masaaki Sawa et al; Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase, J.
Med.
Chem.
2021, 64, 14129-14141
.
2.
https://clinicaltrials.
gov/ct2/home
.
3.
Gloria British Drug News-Who is the leader in BTK inhibitors? The market size in 2026 may be close to 20 billion U.
S.
dollars;