What is the future of kinase inhibitors in the past two decades?

Since imatinib was approved in 2001, more than 70 new kinase inhibitor drugs have been approved.

Introduction to protein kinases

Protein kinases are a class of enzymes that catalyze protein phosphorylation reactions.

Phosphate group is a kind of signal that can be used to transmit information.

The kinase domain is some protein fragments, and kinase inhibitors prevent or slow down the activity of the kinase domain.

Kinase inhibitor development

Imatinib is the first inhibitor drug approved to inhibit specific kinases.

In 2002, the EGFR tyrosine kinase inhibitors Gefitinib and Erlotinib were subsequently approved for the treatment of non-small cell lung cancer.

In the tumor environment characterized by specific molecules, the obvious effects of BCR-ABL and EGFR inhibitors can be observed, which have affected the treatment of cancer in the past 20 years, and promoted the development of cancer treatment in the direction of precision treatment.

The picture below shows the memorabilia about the development and approval of kinase inhibitors in the past 20 years.

Twenty years of ups and downs, the development of kinase inhibitors has not been completely smooth.

Resistance to kinase inhibitors can be roughly divided into congenital and acquired resistance.

Acquired drug resistance usually affects the binding of a drug to its target.

Take imatinib as an example.

The median survival period of untreated CML is only three years.

The resistance mechanism of imatinib can be classified as dependent on BCR-ABL or independent.

Among them, BCR-ABL-dependent processes, especially point mutations, are the most common mechanism of imatinib resistance in CML.

Kinase inhibitor development trend

Improve the next generation based on existing targets

The selection of kinase targets roughly follows two steps.

Earlier examples of iterative TKI inhibitor drugs are nilotinib and dasatinib, which are more effective BCR-ABL inhibitors than imatinib and can inhibit mutants resistant to imatinib Afterwards, Bosutinib, which has longer progression-free survival (PFS) and overall survival (OS) than them, was approved as the first-line treatment of CML as the second-generation inhibitor of BCR-ABL.

Lapatinib is another next-generation inhibitor that not only targets the EGFR receptor, but also targets the closely related HER2, which makes it approved for breast cancer.
Recently, more effective and specific HER2 inhibitors neratinib and tucatinib have been approved for breast cancer.

Inhibit the direction of angiogenesis

Such drugs achieve the therapeutic effect by destroying the blood vessels of the tumor and "starving" the tumor to death.
Examples of this are the early sorafenib and sunitinib, and the second-generation pazopanib and cabotinib.
Although it was later discovered that these drugs have multiple targets because they inhibit multiple kinase types, Therefore, the conclusion of whether it works by inhibiting blood vessels remains to be further explored.

VEGF/VEGFR is an angiogenesis signal pathway, which plays a key role in the formation of blood vessels.
The most powerful evidence in this regard comes from the success of the VEGF antibody bevacizumab (Avastin).
Bevacizumab was the seventh largest in the world in 2018.
The best-selling drugs are used to treat a variety of solid tumors.

Direction of multi-target inhibition

For example, ibrutinib, which is used to treat Waldenstrom's macroglobulinemia and diffuse large B-cell lymphoma of the ABC subtype, was originally thought to work by inhibiting Bruton's tyrosine kinase, but it was later found to be able to inhibit both at the same time.
Hematopoietic cell kinase.
To take another example, crizotinib was first developed to target TKI, and it was later discovered that it is also a potent inhibitor of ALK and ROS1, which allows crizotinib to be approved for other indications.

Therefore, this is also an important research and development focus.
Existing target inhibitors can also inhibit other targets.
Through the discovery of new targets, the scope of application of drugs can be expanded to treat different cancers, or to enhance specific cancers.
For example, afatinib targets HER2 and EGFR in lung cancer, and palbociclib targets CDK4 and CDK6 in breast cancer.

Combine with immune checkpoint inhibitors

PD1/PDL1-targeted immune check inhibitors can block this signaling pathway to enhance the ability of the immune system and combat the immune escape of tumor cells.
For details, please see PD-1 / PDL-1 inhibitors in cancer immunotherapy Current and future outlook

Considering the important role of angiogenesis in the immunosuppressive microenvironment, the combined use of VEGFR inhibitors and antibodies targeting PD1/PDL1 is also an emerging strategy.
For example, whether the combination of axitinib and pembrolizumab can improve renal cell carcinoma is currently underway.

In addition to inhibiting blood vessels, certain kinase inhibitors can also stimulate the immune response by regulating the tumor microenvironment, such as preventing PD1 overexpression to enhance T cell infiltration.
The combination of such kinase inhibitors and immune checkpoint inhibitors can produce a synergistic effect, but At the same time, there is also a place that cannot be ignored is that such a combination will lead to enhanced cytotoxicity, such as the combination of osimertinib and PD1 inhibitor durvalumab or the combination of crizotinib and nivolumab.
Pending further evaluation.

Targeting the PI3K pathway

Activation hotspot mutations in PI3Kα (such as E545K, H1047 and E542K mutations, or deletions in the gene encoding PTEN) are often directed to carcinogenesis, which makes PI3K the focus of drug discovery.
However, so far, there has been limited success in developing approved drugs for PI3K.

Idelalisib, a PI3Kδ specific inhibitor expressed in B cells and T cells, is approved for relapsed follicular B cell non-Hodgkin’s lymphoma (FL), relapsed chronic lymphocytic leukemia (CLL) and relapsed small Lymphocytic lymphoma (SLL).
Followed by the next-generation inhibitors copanlisib (for relapsed FL) and duvelisib (for CLL, SLL and FL).

The lack of drugs targeting PI3K may be related to the inability to solve the toxicity caused by the inhibition of this pathway, because this pathway is very important for maintaining normal homeostasis function, so how to develop highly selective inhibitors is what researchers need A difficulty in the strategy.

Targeting the MAP kinase cascade through combination therapy

Such a layered activation pathway drives cell proliferation or differentiation, and kinase mutations in this cascade reaction can lead to cancer.
Such mutations are often observed in some cancers such as lung cancer.

to sum up

Over the next 20 years, oncology will continue to dominate the field of kinase drug discovery.
So far, only 50 of the 500 protein kinases encoded by the human genome have been targeted to treat cancer.
In the future, in addition to the discovery of new targets, issues such as drug resistance and selectivity must be addressed.
Reasonably design the range of new kinase inhibitor combinations, and try a variety of combinations of kinase inhibitors and other treatments.
In the next 20 years, the development of new kinase inhibitors has great potential and is expected to become a major growth area.

references:

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General Introduction to Medicinal Chemistry, written by Guo Zongru.

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Roskoski, R.
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A historical overview of protein kinases and their targeted small molecule inhibitors.
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