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BTK（Bruton’s tyrosine
kinase), the Bruton tyrosine protein kinase, is a member of the non-receptor tyrosine kinase Tec family and is expressed
in all hematopoietic cells (such as B cells and myeloid cells) except T cells and natural killer cells.
BTK is a key molecule that connects B cell receptor (BCR) signaling, chemokine receptor signaling, and Toll-like receptor (TLR) signaling, and plays a key role
in regulating B cells.
BTK can directly interact with 5 different molecules to promote cell proliferation, antibody secretion and pro-inflammatory cytokine production, thereby regulating B cell adhesion, migration and tumor microenvironment
.
Due to its broad and critical physiological role, BTK is an attractive therapeutic target in the treatment of autoimmune diseases and B-cell malignancies
.
Schematic diagram of the role of BTK in the signal pathway
Source: Reference source 1
BTK inhibitor (BTKi) can block the activation of BTK by covalently binding to the Cys-481 site on BTK, thereby inhibiting the occurrence and development of B cells, and is a hot spot
for the development of B cell malignant tumors and autoimmune diseases.
Since the structure and function of BTK was defined in 1993, the scientific community has done a lot of research on it
.
However, it was not until 20 years later, in 2013, that ibrutinib, the first selective BTK inhibitor, was approved by the FDA and jointly developed
by Johnson & Johnson and AbbVie.
The launch of ibrutinib has revolutionized the treatment of B-cell malignant tumors
.
Ibrutinib is a highly potent and highly selective oral small molecule BTK inhibitor that irreversibly inhibits BTK activity
by highly specific covalent binding to cysteine-481 (C481) at the BTK active site.
However, ibrutinib also inhibits multiple targets such as EGFR and TEC, resulting in off-target effects, which can lead to ibrutinib with side effects
such as rash, atrial fibrillation, diarrhea and bleeding, and hypertension.
In order to solve the problems of ibrutinib side effects, pharmaceutical companies have developed second-generation BTK inhibitors
.
Up to now, a total of 5 BTK inhibitors have been approved for marketing worldwide, except for ibrutinib, the remaining four are second-generation BTK inhibitors, namely: AstraZeneca's Abrutinib (approved in 2017), BeiGene's Zanubrutinib (approved in 2019), Ono Pharmaceutical/Gilead's tirabrutinib (approved in 2020), InnoCare's orelabrutinib (approved in 2020).
At present, the overall market size of BTK inhibitors has exceeded 10 billion US dollars
.
Among them, ibrutinib has been in the top global sales since its listing, and has been listed in the top global sales for many years
200 small molecule drugs
.
In 2020, ibrutinib's global sales were $9.
442 billion, accounting for 94.
4%
of the market.
Since the above approved BTK inhibitors are covalent BTK inhibitors, the mechanism of action is to irreversibly inhibit the antitumor effect
of BTK by binding to BTK C481.
Therefore, the defect is that after long-term medication, the C481 site faces the risk of mutation, serine replaces cysteine (C481S), the mode of action of inhibitors and BTK is weakened from irreversible binding to reversible binding, and acquired drug resistance occurs
.
In order to overcome the problem of drug resistance, pharmaceutical companies have begun to develop a new generation of BTK inhibitors
.
At present, its R&D strategy mainly includes the development of non-covalent BTK inhibitors and BTK PROTACs
.
01 Non-covalent BTK inhibitors
01 Non-covalent BTK inhibitorsNon-covalent BTK inhibitors do not rely on binding to the C481 site, but bind to the BTK protein by hydrogen bonding, so they are expected to effectively overcome the resistance problems
in the previous generation of products.
Schematic diagram of non-covalent BTK inhibitor binding to the target
Source: Reference source 2
At present, giants such as Eli Lilly and Merck have devoted themselves to the research and development
of non-covalent BTK inhibitors.
LOXO-305（Pirtobrutinib）
LOXO-305 (Pirtobrutinib), developed by Eli Lilly's Loxo Oncology, is a non-covalent BTK inhibitor
.
It is to BTK
The C481 mutant has inhibitory activity, and its non-covalent inhibition mechanism allows it to inhibit BTK activity
even with high BTK turnover.
In a study called BRUIN, a total of 618 patients were included, including 296 patients with chronic lymphocytic leukemia (CLL)/small cell lymphoma (SLL), 134 patients with mantle cell lymphoma (MCL), and 188 patients
with other B-cell lymphoma.
The results showed that among 252 patients with CLL/SLL whose efficacy could be evaluated by previous BTK inhibitors, the objective response rate (ORR) was 68% (95% CI: 62~74), including 2 complete response (CR), 137 partial response (PR), 32 partial response with lymphocytosis (PR-L), and 62 stable disease (SD).
Efficacy of LOXO-305 in the treatment of CLL/SLL
Source: Reference source 3
In patients with MCL, LOXO-305 also performs well
.
In a population of 100 evaluable patients previously treated with BTK inhibitors, the ORR was 51%; For 11 patients who were treated with BTK inhibitors, the ORR reached 82%.
The median time to remission also reached 18 months
.
Effect of LOXO-305 in the treatment of MCL
Source: Reference source 3
MK-1026（nemtabrutinib）
MK-1026 (nemtabrutinib, code ARQ531) is an oral, potent reversible BTK inhibitor
developed by ArQule.
As a non-covalent BTK inhibitor, MK-1026 is designed to bind BTK reversibly, which can maintain its activity under the condition of C481 acquired drug-resistant mutations, and is highly active not only against wild-type BTK, but also highly active against BTKs carrying C481 mutations, avoiding the development of
drug resistance.
In December 2019, Merck announced the acquisition of ArQule for $2.
7 billion, acquiring a number of products
, including MK-1026.
Ibrutinib and MK-1026 have different modes of binding to BTK proteins
Source: ArQule official website
In a Phase I clinical trial, a total of 47 patients with relapsed/refractory B-cell malignancies were treated
with varying doses of MK-1026.
The results showed: at the dose > 65 mg
At QD (once daily), PR was achieved in 8 of the 9 patients with chronic lymphocytic leukemia who could be evaluated, and 7 of the 8 who achieved remission carried the BTK-C481S mutation
.
Phase II clinical results reported at the 2021 ASH Congress showed that 51 CLL/SLL patients participated in the Phase II dose expansion study of MK-1026, of which 84% had previously received BTK inhibitor therapy and 63% carried BTK-C481S mutation
.
The results showed that the ORR of 38 patients with evaluable efficacy was 58%, of which 1 had CR, 12 had PR, and 9 had partial remission
with lymphocyte elevation.
At present, Eli Lilly's LOXO-305 is slightly better than Merck's MK-1026 in hematological tumors, but there are still variables in the future, and the efficacy and safety of non-covalent inhibitors need to be verified by time
.
02 BTK-PROTAC
02 BTK-PROTACSince 2001, PROTAC (Targeted Protein Degradation Technology) has attracted the attention
of scientists.
The PROTAC molecule consists of three parts: one end is the ligand that binds to the target protein, and the other end is the E3 ubiquitin ligase recognition structure, and the two are connected
by linkers.
PROTAC molecules induce ubiquitination of target proteins within cells, which are then recognized and degraded
by the proteasome.
Mechanism of action of PROTAC molecules
Source: Arvinas official website
Unlike small molecule BTK inhibitors, BTK-PROTAC drugs do not need to bind tightly and for a long time to degrade
the pathogenic target.
By adopting this method of disappearing pathogenic targets, the problem of BTK drug resistance will be solved
naturally.
At present, BTK-PROTAC developed by several enterprises at home and abroad has entered the clinical stage
.
HSK29116
The HSK29116 powder independently developed by the domestic enterprise Haisco is the world's first BTK to be declared for clinical trials
PROTAC products
.
HSK29116 was approved for clinical use in China in April 2021 for B-cell lymphoma
.
In April 2022, the clinical trial application for HSK29116 was approved by the FDA
.
On the one hand, HSK29116 can directly inhibit BTK activity by specific binding to BTK; On the other hand, it can induce BTK ubiquitination labeling and degrade it through the proteasome pathway, thereby blocking the transmission of BCR signaling pathway, inhibiting the growth and proliferation of B-cell lymphoma cells, and playing a dual anti-tumor effect
.
BGB-16673
BeiGene's BTK-PROTAC product BGB-16673 also began a global Phase I clinical study
in August.
Preclinical models have shown that BGB-16673 can overcome C481S resistance, which is expected to break through the problem
of resistance to zebratinib and other BTK inhibitors in patients.
NX-2127
In addition to HSK29116 and BGB-16673, BTK-PROTAC products currently entering the clinical stage include foreign Nurix
NX-2127
by Therapeutics.
NX-2127 drives the degradation of targets BTK and IKZF3 through ubiquitination and proteasome degradation, and can theoretically overcome the problem
of drug resistance including BTK covalent inhibitors (cBTKi) and non-covalent inhibitors (ncBTKi).
At the just-concluded 2022ASH Annual Meeting, developers reported on the results of
a multicenter, open-label Phase I NX-2127-001 study of NX-2127.
As of June 16, 2022, a total of 28 patients were enrolled in cohorts
with dose levels of 100 mg, 200 mg and 300 mg, respectively.
Among them, 17 patients with CLL had a median treatment line of 6, and all patients were treated
with BTK inhibitors.
At day 22 of cycle 1, a mean 86% BTK degradation rate was observed in all patients and an average BTK degradation rate of 83% in 12 CLL patients, with an ORR of 33%, and the ORR increased with longer follow-up (ORR: 16.
7% at 2 months, 42.
9% at 4 months, and 50% at 6 months).
More importantly, patients refractory to BTK/BCL-2 inhibitors and patients who progressed after treatment with non-covalent BTK inhibitors also showed some degree of remission
.
03 Summary
03 SummaryAt present, the development of BTK-PROTAC is still in the early stages, and the road ahead is by no means easy
.
At present, with the development of technology, the iterative research and development of BTK inhibitors is still in progress
.
The new generation of BTK inhibitors must not only show good efficacy, but also be better in safety and tolerability
.
In addition to improving the specificity of covalent irreversible BTK inhibitors, the development of new non-covalent BTK inhibitors and BTK-targeted protein degraders to overcome the problem of drug resistance is a major research and development direction
in this field.
At present, many pharmaceutical companies at home and abroad have entered the golden track of BTK, and the war is about to break out
.
Reference source
Reference sourceReference source
1、Buggy, J.
J.
, & Elias, L.
Bruton Tyrosine Kinase (BTK) andIts Role in
B-cell Malignancy.
International Reviews of Immunology, 2012, 31(2):
119–132.
J.
, & Elias, L.
Bruton Tyrosine Kinase (BTK) andIts Role in B-cell Malignancy.
International Reviews of Immunology, 2012, 31(2): 119–132.
2.
Discovery of new BTK inhibitors against rheumatoid arthritis[D].
East China Normal University,2018.
Discovery of new BTK inhibitors against rheumatoid arthritis[D].
East China Normal University,2018.
3、Mato A, et al.
Pirtobrutinib, A highly selective, non-covalent (reversible)
BTK inhibitor in previously treated CLL/SLL: Updated results from the Phase 1/2
BRUIN study.
ASH 2021.
/
Pirtobrutinib, A highly selective, non-covalent (reversible) BTK inhibitor in previously treated CLL/SLL: Updated results from the Phase 1/2 BRUIN study.
ASH 2021.
/
4、ArQule Announces Final Phase 1 Clinical Data for Its Reversible BTK
Inhibitor, ARQ 531, at the American Society of Hematology 2019 Annual Meeting.
Retrieved December 9, 2019, from
Retrieved December 9, 2019, from 5、Eric Wang, Xiaoli Mi, Meghan C.
Thompson, etal.
Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors.
N Engl J Med 2022; 386:735-743.
5、Eric Wang, Xiaoli Mi, Meghan C.
Thompson, etal.
Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors.
N Engl J Med 2022; 386:735-743.
