[Transfer] G12C mutation is difficult to create "medicine king", KRAS target needs to break through the adaptive ceiling

[Transfer] G12C mutation is difficult to create "medicine king", KRAS target needs to break through the adaptive ceiling

Source: amino observation/Cai Jiu

One year ago, Anjin KRAS G12C inhibitors were approved to completely rewrite the history of KRAS targets to paddish, making the market inspiring.

Because of this, many domestic pharmaceutical companies have been poured into this field. In addition to the leading pharmaceutical companies such as Ding Ding Pharmaceuticals and Greaty, it also includes Yifang Biological, Jinfang Biology, Qinhao Biological, Beida Pharmaceutical, Junshi Biology, and Elis.

It seems that the KRAS G12C inhibitor has become another market that does not lose PD-1 in the market that is not inferior to PD-1. Does this mean that the KRAS target hasn't watched it? The answer is obviously not the case.

As the first carcinogenic gene discovered by humans, KRAS targets have bid farewell to the history of "non -medicine", but still have a long way to go.

Because the KRAS G12C mutation is only a category of this target. For any pharmaceutical company, it is difficult for the KRAS G12C inhibitors to become a "medicine king" alone.

The bubble itself is not terrible. For any industry, bubbles are coexistence and disadvantages. The advantage of the foam is that it will attract a lot of resources to invest and promote the rapid development of the industry.

The same is true for KRAS targets that need to break through the ceiling. After the KRAS G12C inhibitor, domestic pharmaceutical companies began to lay out a wide range of KRAS targets.

Comparative, just beginning.

/ 01 /

Big target of extreme division

As the first carcinogenic gene in human history, RAS gene mutations are related to about 20%of tumor. The RAS gene mutation will continuously stimulate cell proliferation and migration, leading to tumors, commonly in the field of pancreatic cancer, colorectal cancer, and lung cancer.

RAS gene mutations are divided into multiple types, including KRAS, NRAS, Hars. Among them, KRAS is the most common type of mutation, accounting for about 85%.

Under simple conversion, the KRAS gene mutation is about 17%of tumor. Judging from this figure, the KRAS gene mutation is undoubtedly a big target.

But things are not so simple. Although the target of KRAS is large, it is difficult to focus. Because there are too many mutations sites, the KRAS gene mutations have been divided into many sequential sets, including G12C, G12D, G13D mutations, and so on.

In the case of extreme division, the scale of the patient group of the KRAS targets is not large.

Take the US market as an example. As shown in the figure below, although the number of patients with tumors in the United States every year, the number of KRAS mutations exceeds 100,000. However, the highest proportion of G12D mutations, the number of new patients is only 51,000, and there are fewer such as G12V and G12C.

In addition, these mutant patients exist in different tumors, making the market more dispersed. For example, the hottest KRAS G12C inhibitor currently developed is the main patient in the field of lung cancer. This has caused the difficulty and cost of the development of pharmaceutical companies.

The same is true in China. Because of the differences in population, compared with the KRAS G12C mutation in overseas countries, it is a more rare type. According to the Yifang Biological prospectus, KRAS G12C, one of the most common mutation sites in China, is only about 43,000 in 2020.

These 43,000 people also exist in segmented market segments such as lung cancer, colorectal and bile duct cancer. In terms of incidence, lung cancer is about 4.3%, colorectal cancer is about 2.5%, and cholecoritic cancer is 2.3%.

Obviously, for pharmaceutical companies, if you want to stand firm in KRAS targets, you need to meet the needs of more patients to break through the ceiling caused by the splitting of the target. Of course, it is not easy to do this.

/ 02 /

Break the dawn one by one

At present, although patients with non -small cell lung cancer who are targeted at KRAS G12C mutations have made breakthroughs, other indications and other types of mutations still require pharmaceutical companies to continue to explore.

For a long time, the path of targeted patent medicine for KRAS gene mutations is quite bumpy. The core reason is that it is difficult for KRAS protein, whether it is directly "killing" gene mutations or inhibiting its replication function.

KRAS protein is a very small molecule. The surface is relatively smooth. It is difficult to find a "pocket" for drug -binding and cannot be destroyed directly. KRAS has super affinity for the nucleotide GTP that provides energy, so it is difficult for ordinary drugs to be with. GTP competition, indirectly hit KRAS protein.

To some extent, the birth of the KRAS G12C inhibitor is lucky. Because scientists have discovered that the KRAS G12C mutation point is from glycine to cysteine. The combination of this mutation position and irreversible inhibitors destroys Switch-I and Switch-II pockets, so that we have the opportunity to take advantage of the opportunity Essence

Despite this success, because other mutations are not cysteine. In the case of lack of low -intimidation of non -cysteine, the covalent drugs of other non -cysteine ​​hot -spiced mutations targeting KRAS still need to be developed.

Of course, things are artificial. With the breakthrough of the KRAS G12C inhibitor, it also brings people more inspiration. Today, this success may be copied to the KRAS G12S mutant.

A few days ago, Professor KEVAN M. Shokat, who made breakthrough contributions in the "non-medicine" of KRAS's "incomparable medicine", published the latest research on Nature Chemical Biology, showing that through the logic of specific co-price suppression, the structure of β-lactone has been successful. Add on the skeleton of Mirati KRAS G12C inhibitor Adagrasib. After many optimized inhibitors, the specificity can be combined with the KRAS G12S mutant price, significantly reducing the activity of the mutant, and at the same time, it will not affect the wild -type KRAS protein.

Although this study focuses on the KRAS G12S mutant, they believe that this strategy adds a new tool to targeting the lingine, which can be used to target other targets carrying derivedine. As for whether it is feasible, it takes time to verify.

In contrast, non -co -prices may be a more promising path. In fact, Mirati has made progress aiming at the KRAS G12D mutation.

On the basis of Adagrasib, Mirati uses pyridine pyrine skeleton to further screen and optimize. A selective non -covalent KRAS G12D inhibitor that is finally obtained has entered the clinical stage.

In China, for the KRAS G12D mutations, there are also research on Pharmaceutical companies including Hengrui Pharmaceutical, Elis, Yifang Biology, in which Hengrui Pharmaceutical KRAS G12D inhibitors have been approved clinically a few days ago.

Taken together, although only the KRAS G12C inhibitors have been padded with Kars mutations at present, drugs that are for other mutations are gradually ushered in the dawn of victory.

/ 03 /

Pan Kars breakout war has begun

In addition to breaking one by one, some pharmaceutical companies have greater dreams -hoping to break through through pan -Kars drugs. Compared to breaking one by one, there are more development strategies for pan -kars drugs.

At present, the most popular direction is to curb pan -KRAS protein activity by blocking the upstream pathway of the KRAS. Because of this, the SOS1 or SHP2 target on the upstream of KRAS, because the mechanism is clear and the characteristics of more difficulty in the patent medicine have become the fragrance of pharmaceutical companies.

For example, SHP2 inhibitors have attracted many domestic pharmaceutical companies, including Gakos, Nuo Chengjianhua, Shenghe Pharmaceutical, Beida Pharmaceutical, Qinhao Pharmaceutical and other companies are conducting research.

However, it is unknown to curb Kars mutations through upstream pathways, after all, the human mechanism is too complicated.

Although the KRAS gene mutations are closely related to the upstream pathway SHP2 and SOS1, in addition, it is also supported by other cell proteins. It may not only bring deep and lasting clinical benefits to the upstream pathway.

At present, the clinical clinical of all pharmaceutical companies is still in the early stages, and the future is full of variables.

However, even if the road that is indirectly curbed is unreasonable, the problem -solving ideas that directly cover various types of KRAS mutations are still hopeful.

At present, overseas pharmaceutical companies such as Berlingin Gelham and Revolution Medicines are looking for answers along this idea, and the logic is basically consistent: by directly curbing the RAS gene to achieve the purpose of blocking RAS heterogenes at the same time.

In addition, with the advancement of Protac technology, we can see more possibilities. Because Protac drugs do not need to combine with the target protein for a long time, they can grasp the target protein and degrade it. In this way, the problem of KRAS targets is inconvenient.

Of course, whether it is directly curbing the RAS gene, or through the Protac technology curve to save the country, it is also necessary to prove itself through solid clinical data like SOS1 inhibitors or SHP2 inhibitors.

/ 04 /

Summarize

Although it is still difficult to overcome KRAS targets completely, after the KRAS G12C mutation field ushered in a breakthrough, the research and development of drugs against KRAS mutations has ushered in the golden age.

In the future, I believe we can definitely see Pan KRAS drugs and the two types of drugs for a single mutation to compete on the same stage, bringing better treatment choices to global patients.

This does not mean that which technical route is the only answer. Just like Revolution Medicines, while developing pan -KRAS drugs, it is also extensively layout of drugs with a single mutation. This is the key to supporting its market value of over 2 billion US dollars.

For drugs for KRAS mutations, the core is that they can have deep and persistent inhibitory effects in the group of patients who are clearly defined, and these elements are the most critical.

How to weigh many factors and meet the clinical needs of patients with KRAS gene mutations, and establishing their own moats in their own pharmaceutical companies.

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