July 23, 2024

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The latest progress and future directions of kinase inhibitors

The latest progress and future directions of kinase inhibitors

 

The latest progress and future directions of kinase inhibitors.  Protein kinases regulate almost all aspects of cells, and abnormal expression levels or mutations can lead to cancer and other diseases.

Since the approval of imatinib in 2001, 76 kinase inhibitors have been approved for marketing. The success of these pioneering compounds, especially the amazing efficacy of imatinib after its entry into clinical trials in 1998, has changed people’s views on protein kinases as drug targets; currently, hundreds of protein kinase inhibitors have been developed And tested it on humans.

The latest progress and future directions of kinase inhibitors
Pink is tyrosine kinase; blue is serine/threonine specific protein kinase

 

 


The clinical impact of kinase inhibitors

The development and approval of kinase inhibitors has changed the clinical treatment of a variety of malignancies including CML, GIST, melanoma and NSCLC. Compared with chemotherapy, targeted therapy (for NSCLC with EGFR mutations and ALK rearrangement) greatly improves the response rate and PFS, and reduces adverse reactions.

In chronic myeloid leukemia, conventional treatment has been replaced by BCR-ABL inhibitors, and allogeneic bone marrow transplantation is now only used for multidrug resistance or advanced disease. The clinical application of systemic chemotherapy for GIST or BRAF mutant melanoma has almost disappeared; in non-small cell lung cancer, genotype-directed therapy including kinase inhibitors has replaced systemic chemotherapy as the initial treatment for patients with advanced non-small cell lung cancer.

Another feature of kinase inhibitors is that they can penetrate the blood-brain barrier (BBB) ​​and are used to treat brain metastases and/or leptomeningeal diseases; chemotherapeutic drugs rarely pass through the blood-brain barrier, and the long-term side effects of radiotherapy can be devastating of.

The latest progress and future directions of kinase inhibitors

 

 

Kinase inhibitor resistance

Although approved kinase inhibitors have brought benefits to many cancer patients, these drugs do not cure cancer, and most tumors can only delay tumor progression. Advanced tumors usually find a way to escape target inhibition, leading to drug resistance. Since the first kinase-inhibiting drugs came out, resistance has been observed, and effectively dealing with this problem has become a major challenge.
The resistance of kinase inhibitors can be roughly classified into congenital or primary resistance. Acquired resistance mechanisms include secondary mutations of target proteins, “bypass” activation, or phenotypic transformation. Mutations in the kinase domain that cause drug resistance include goalkeeper, solvent pre-mutation, and DFG loop mutations.

The latest progress and future directions of kinase inhibitors

 

 

Research Progress of Kinase Inhibitors

In the past 20 years, due to several key technological advancements, the design of kinase inhibitors has been significantly improved.

  • First, after sequencing the human genome, more than 500 protein kinases (human kinome) were comprehensively classified and annotated and subdivided into several sub-families, which led to a comprehensive understanding of the relationship between the kinome and promoted A phased change in the way of kinase drug discovery.
  • Second, due to advances in automated, trace kinase activity testing methods, kinase profile testing has become cheaper. This enables drug developers to perform routine analysis on the main targets of inhibitors and off-target kinases, so that lead compounds with poor selectivity can be discarded at an early stage, and then help guide the selective improvement of key series of compounds. Broad-spectrum kinase inhibitors have obtained new clinical opportunities, and adverse reactions can be reasonably explained.
  • Third, driven by structural genomics, there are more and more high-resolution structures of kinase catalytic domains, which enables structural chemistry, computational chemistry, and fragment-based drug design methods to be routinely integrated into drug discovery.
  • Fourth, the elucidation of the drug resistance mechanisms observed in patients will help to find development opportunities for next-generation inhibitors and grasp the characteristics of clinical needs.

So far, protein kinases that drive the cell division cycle, such as PLK, aurora kinase, and some cyclin-dependent kinases, have not yet developed clinically useful inhibitors due to insufficient therapeutic benefits. For these targets, continuous medicinal chemistry efforts are required to develop selective inhibitors with better tolerance.

Another important issue in the field of kinase inhibitors is how to develop drugs that cross the blood-brain barrier: because with the prolonged survival time of advanced cancer patients, brain metastasis is a common clinical problem. Balancing and maintaining all the properties of the drug, such as potency, selectivity, and optimal blood-brain barrier permeability, remains a major challenge.

 

 


Non-cancer kinase inhibitor

Smooth muscle relaxation and immunosuppression

The Rho kinase inhibitor Fasudil (AT877, HA107) has shown efficacy in the treatment of cerebral vasospasm. It was approved for this purpose in Japan in 1995, and was later approved in China, but has not yet been approved in the United States or Europe. Fasudil was developed from a class of molecules that were originally identified as calmodulin antagonists and was later found to inhibit several protein kinases of the AGC subfamily including Rho-dependent kinases, which lead to myosin P light chain Decreased phosphorylation, increases smooth muscle relaxation, thereby dilating blood vessels.

The target of rapamycin is FK506 binding protein (FKBP), and the FKBP-rapamycin complex has been proven to be an effective and specific inhibitor of the TORC1 protein kinase complex. The immunosuppressive properties of rapamycin were approved in 1999 as an immunosuppressant for kidney transplant recipients, and later used to treat lymphangiomyomatosis, a rare lung disease.
Inflammation and autoimmune diseases

Inflammatory diseases and autoimmune diseases, including arthritis, asthma, colitis, fibrosis, systemic lupus erythematosus (SLE), psoriasis, and sepsis, are often related to the overproduction of inflammatory mediators caused by immune system disorders. Some protein kinases are related to the function of intracellular cytokines and the cells that produce them, and become potential targets for the treatment of these diseases; but because the normal functions of cytokines play a role in fighting microbial pathogens, such inhibitors face unacceptable risks of infection .

Janus kinase (JAK) inhibitor tofacitinib was approved in 2012 for the treatment of moderate to severe rheumatoid arthritis. This is the first drug developed by targeting specific protein kinases outside of the cancer field, and also the first An oral active drug for treating rheumatoid arthritis for more than 50 years. Tofacitinib was subsequently approved for the treatment of psoriatic arthritis, ulcerative colitis, and juvenile idiopathic arthritis. Approximately 12 other JAKitinibs are undergoing clinical trials. But tofacitinib treatment increases the risk of microbial infections, especially upper respiratory tract infections. Recently, 1% of patients receiving treatment

 

increased the risk of venous thromboembolism.

Protein kinases that target the production of inflammatory cytokines have attracted more and more attention. An interesting candidate kinase is IRAK4 (Interleukin 1 Receptor Associated Kinase 4), which is required for the production of pro-inflammatory cytokines and chemokines by Toll-like receptors (TLRs). It expresses small IRAK4 kinase inactive mutants. Mice are protected in a variety of inflammatory and autoimmune disease models, and IRAK4 inhibitors prevent SLE autoimmunity and autoinflammation in mouse models related to human SLE. At least four compounds that specifically inhibit IRAK4 or IRAK4 and IRAK1 dual inhibitors (PF-06650833, BAY1834845, BAY1830839 and CA-4948) are currently undergoing phase I/II clinical trials for inflammation and autoimmune diseases.

The potential problem of IRAK4 inhibitors causing increased susceptibility to infection by microbial pathogens has been resolved through a 30-year study. Infants with IRAK4 deficiency are extremely susceptible to purulent bacterial infections. Even if they use broad-spectrum antibiotics every day, half of them die before the age of 8. The fascinating thing is that these people no longer die at the age of 8, and invasive bacterial infections gradually decrease. They rarely appear after the age of 20. They also have normal resistance to common fungi, parasites, viruses and many other types of bacteria. force. Therefore, the important role of IRAK4 in humans seems to be limited to protecting young children from a few bacterial infections, indicating that IRAK4 inhibitors can be safely applied to adults. .

Inhibition of protein kinase SIK subfamily members can enhance the production of IL-10, convert macrophages from inflammatory M1 to anti-inflammatory M2b state, promote the regression of inflammation and the repair of damaged tissues after infection, suggesting that SIK inhibitors can be used in inflammatory diseases The treatment has potential application value. SIK inhibitors are currently undergoing advanced clinical trials for rheumatoid arthritis, ulcerative colitis, psoriasis and other diseases. SIK inhibitors also show preclinical activity in fibrotic disease models.

 

Alzheimer’s disease

The p38 kinase inhibitor neflamapimod (formerly VX745) is used to treat Alzheimer’s disease. This compound reversed amyloid-β (Aβ)-induced synaptic dysfunction and loss, reduced the production of β-Alzheimer’s disease mouse models, and cognitive impairment rats in the Morris water maze (MWM) test Performance improvement. Some TKIs that passed the BBB and passed Phase I/II trials have also been re-used to treat Alzheimer’s disease, including saracitinib (previously AZD0530) and the BCR-ABL inhibitor nilotinib.

Glycogen synthase kinase 3 (GSK3) is one of the protein kinases that phosphorylate Tau; the hyperphosphorylation of tau accumulates the hallmarks of Alzheimer’s disease and other tau diseases. The GSK3 inhibitor tideglusib192 was found to reduce the hyperphosphorylation of tau protein and other Alzheimer’s disease markers, such as amyloid deposition, neuronal loss and gliosis in the mouse brain. It can also reverse Alzheimer’s Spatial memory deficits in a mouse model of Zheimer’s disease. Tideglusib was well tolerated in I/II clinical trials. A pilot, double-blind, randomized phase 2 trial (NCT00948259) of 30 patients with mild to moderate Alzheimer’s disease showed a positive trend in multiple cognitive benefit tests; however, one involved 306 The larger phase II trial of a patient with Alzheimer’s disease missed its main cognitive endpoint.

 

Parkinson’s Disease

1% to 2% of Parkinson’s disease worldwide is caused by mutations in the protein kinase LRRK2 gene, although this mutation is more common in certain populations. There is also increased activity of LRRK2 in dopamine-sensing neurons in patients with idiopathic Parkinson’s disease that is not related to mutations. LRRK2 may activate α-synuclein and mitochondrial damage through an oxidative mechanism, leading to endolysosome dysfunction, accumulation of phosphorylated α-synuclein and Parkinson’s syndrome. Therefore, the increase in LRRK2 activity may contribute to the pathogenesis of Parkinson’s disease patients. A small number of LRRK2 inhibitors including DNL201 (Denali) have entered clinical trials.


Other diseases caused by protein kinase mutations

The specific subtype of PKCγ may be related to the pathogenesis of some spinocerebellar ataxia. Increased expression of protein kinase WNK1 or WNK4 (caused by its mutation and other mechanisms) is the basis of Gordon syndrome, which is caused by defective potassium excretion Caused by hereditary hypertension. Hypertension is mediated by WNK-catalyzed phosphorylation and activation of protein kinases SPAK and OSR1, which control the activity of several ion cotransporters.

 

 

The development trend of kinase drugs in the next 20 years

We predict that in the next 20 years, oncology will continue to dominate the discovery of kinase drugs. Although only 50 of the 518 protein kinases encoded by the human genome have been used in cancer treatment so far, we predict that the number of new kinases used in cancer drug development will only increase slightly in recent years because they have been used as specific cancer drivers in recent years. New mutations of factor kinases have not yet been discovered. We believe that the research focus of kinase inhibitors in oncology will mainly focus on how to overcome drug resistance.

We envision that the development trend of next-generation kinase inhibitors will accelerate. This inhibitor has better selectivity, resistance to drug resistance and central nervous system penetration. In addition, we believe that the rational design of new kinase inhibitors and their combinations, the combination of kinase inhibitors and other treatment methods, and research on overcoming and preventing drug resistance will increase.
The role of tumor stromal microenvironment and immunobiology in the protection of cancer cells will be another key area of ​​in-depth research, such as TAM kinases (TYRO3, AXL and MER) and colony stimulating factor 1 receptor (CSF1R) in immune signal transduction Play a key role.

So far, the only rationally designed drug for the treatment of diseases other than cancer is JAK inhibitors. We believe that the number of new protein kinases targeted for the treatment of diseases other than cancer will gradually increase. For example, the GSK3 inhibitor tideglusib is undergoing clinical trials for Alzheimer’s disease; at the same time, it has been found that the inhibition of GSK3 plays an important role in regulating insulin-dependent blood sugar conversion into tissue glycogen. Perhaps GSK3 inhibitors can reduce blood sugar in patients with type 2 diabetes Level of potential.

 

We predict that next-generation antibody approaches will lead to more drug approvals, including bispecific antibodies that block more than one kinase. An example that has shown encouraging data in clinical development is Amifantama (JNJ-61186372), a dual MET/EGFR antibody. Antibody-drug conjugates (ADC) are another exciting future therapeutic platform.

 

We predict that the development technology of small molecule inhibitors will continue to make breakthroughs. For example, in recent years, significant progress has been made in the development of drugs that induce the degradation of specific proteins. PROTAC technology uses chemical entities to guide the degradation of specific proteins mediated by ubiquitination. It must be emphasized that the specific proteolytic destruction of protein kinases is not equivalent to the inhibition of their catalytic activity, because many kinases are multi-domain proteins. When the expression of protein kinase is removed, every domain is eliminated, which can improve efficacy, but can also cause more serious side effects.

 

Both the approved MEK1/MEK2 small molecule inhibitors (trametinib, slumetinib) and the research AKT inhibitor MK2206 are allosteric inhibitors, which block kinase activity by binding to regions outside the catalytic domain. This allosteric inhibitor avoids competition with intracellular ATP to bind to the catalytic site, thereby increasing the potential for the development of more effective and specific inhibitors. Ascinimib is an allosteric ABL inhibitor that binds to the myristoyl binding site of BCR-ABL; in preclinical and clinical studies, this compound has been shown to be effective against resistance mechanisms, including the ABLT315I gating mutation.
In short, the potential for the development of new kinase inhibitors is huge, and we confidently predict that kinase inhibitors will continue to be a major growth area for drug development in the next 20 years!

 

(source:internet, reference only)


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