Nature's in-depth review: the past and future of protein kinase drug development

In 2001, the protein kinase inhibitor Gleevec (imatinib) was first approved by the FDA
.

This is an important breakthrough in targeted anti-cancer therapy and heralds the rise of protein kinase inhibitors in oncology and other therapeutic fields

Overview of approved protein kinase inhibitors

Overview of approved protein kinase inhibitors

The review pointed out that as of May this year, there were 98 small-molecule kinase inhibitors and kinase-targeted biological products approved worldwide
.

It is worth pointing out that in the past 5 years, 37 small molecule kinase inhibitors have been approved by the FDA, accounting for about 15% of all innovative drugs approved by the FDA

▲The timeline for the approval of protein kinase inhibitors (picture source: reference [1])

Different modes and drug design for inhibiting protein kinase activity

Different modes and drug design for inhibiting protein kinase activity

Among the approved small molecule kinase inhibitors, the most common mechanism of action is to inhibit the activity of protein kinases by binding to the ATP binding site of the target
.

Of the 71 small molecule inhibitors approved by the FDA, 63 use this mechanism

▲Two different types of allosteric inhibitors (picture source: reference [1])

Since the EGFR inhibitor afatinib and the BTK inhibitor ibrutinib were approved by the FDA in 2013, 9 small molecule covalent inhibitors have been approved by the FDA to target EGFR mutants or BTK
.

Except for acalabrutinib, all approved covalent kinase inhibitors use acrylamide groups as electrophiles that form covalent bonds

▲The mode of action of bifunctional molecular kinase inhibitor (picture source: reference [1])

The development trend of kinase inhibitors under investigation

The development trend of kinase inhibitors under investigation

Based on the data analysis of ClinicalTrials.
gov, the review authors found that nearly 600 drugs targeting kinases are in the clinical development stage, including 475 innovative small molecule kinase inhibitors and 124 biological products (responded to WuXi AppTec for "kinase inhibitors" , You can get the download link, download the information of more than 600 kinds of kinase inhibitors under development)
.

In the past 5 years, the number of small molecule kinase inhibitors entering clinical development has increased by more than 200%

In the field of cancer, the Aurora kinase family is the kinase family most targeted by therapies under investigation, with 22 drugs entering clinical trials in total
.

The role of these kinases in cell division, and their widespread overexpression in human tumors, has made them a long-standing target of interest for researchers

Currently, the second-generation subtype selective aurora kinase inhibitor is in clinical trials for the treatment of hematological cancers
.

The CDK family contains 20 members and plays an important role in controlling cell cycle changes and regulating transcription

▲Indication distribution of approved kinase inhibitors (picture source: reference [1])

Outside of oncology, more than 40 kinase inhibitors are used in clinical trials to treat immune system diseases, including rheumatoid arthritis, psoriasis, lupus erythematosus, multiple sclerosis and alopecia areata, among which 12 drugs are in phase 3 Clinical development stage
.

Some of the drugs under development are targeted by approved drugs, such as members of the JAK family, but also include new protein targets, such as IRAK4, RIPK1, TPL2 and TYK2

Look to the future

Look to the future

The review pointed out that at least 70% of the human kinases (about 400) have not yet entered the clinical development stage of targeted drugs
.
Moreover, about 30% of kinases do not have any drugs and small molecule compounds that have specific activity against them, and 21 kinases (3%) are currently almost ignorant of them
.
Interestingly, the expression of these less studied proteins changes in a variety of cancer types, so further research on them has potential therapeutic value
.
In order to further expand kinase drug discovery, the author pointed out that we need to further develop effective compound screening and characterization techniques, especially the means to discover new compounds
.
In addition, it is still a challenge to obtain target selectivity to reduce off-target side effects.
In this regard, the development of inhibitors with different binding modes, such as allosteric and covalent inhibitors, and targeted protein degradation agents, may be in the next 20 years.
Plays a key role in the development of kinase drugs
.
Reply "kinase inhibitor" to WuXi AppTec (as shown in the figure below) to get the download link, and download the Excel table summarizing the relevant information of the kinase inhibitor in research compiled by the author
.

Reference materials:

[1] Attwood et al.
, (2021).
Trends in kinase drug discovery: targets, indications and inhibitor design.
Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-021-00252-y

[2] Cohen et al.
, (2021).
Kinase drug discovery 20 years after imatinib: progress and future directions.
Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-021-00195-4