After 40 years of sharpening the sword, what breakthroughs lie behind the conquering of the famous "unmade medicine" target?

▎The KRAS gene mutation edited by WuXi AppTec's content team is one of the first oncogene mutations discovered and the most common oncogene mutation in human cancers.

KRAS gene mutations are found in 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers.

However, KRAS is also one of the most famous "non-drugable" targets because it lacks a "pocket" that binds to small molecule drugs.
In the past few decades, the development of drugs targeting KRAS has repeatedly frustrated.

KRAS’s “unable to drug” property was finally breached last week.
The US FDA accelerated the approval of the KRAS G12C inhibitor Lumakras (sotorasib, formerly known as AMG 510) developed by Amgen.
It became the first targeted specific product.
Anti-cancer therapy for KRAS gene mutations.

What scientific breakthroughs made Lumakras' success? Where will the future of KRAS targeted therapy go? Today, WuXi AppTec's content team will review with readers the history of breaking through KRAS's "non-medicability".

Image source: References [8] reveals the hidden binding "pocket" on KRAS mutants.
In the history of the development of KRAS targeted therapy, a paper published in the top academic journal "Nature" in 2013 is considered to change the development of therapy One of the groundbreaking studies of the trend.

In this study, a research team led by Professor Kevan M.
Shokat of the University of California, San Francisco (UCSF) discovered a series of compounds that specifically bind to KRAS G12C mutants.

The crystallographic study of the complex of the compound and KRAS G12C mutant found that there is a "pocket" on the KRAS G12C mutant protein that can bind to small molecule drugs.

The combination of small molecule compounds with this "pocket" can "lock" the KRAS G12C mutant in an inactive conformation, thereby providing a potential target for inhibiting the activity of the KRAS mutant.

The study of the previously undiscovered hidden binding "pocket" on the KRAS G12C protein in this paper provides a new direction for the development of KRAS targeted inhibitors.

Lumakras developed by Amgen and multiple KRAS G12C covalent inhibitors currently in clinical development all target this binding "pocket.
"
Professor Kevan M.
Shokat also co-founded Araxes Pharma with Dr.
Troy Wilson, Dr.
Liu Yi and Dr.
Ren Pingda to continue the development of KRAS G12C targeted inhibitors.

Dr.
Frank McCormick, a famous oncologist at UCSF, joined the company's scientific advisory board.

The development of KRAS G12C covalent inhibitors However, the discovery of pockets that can bind to KRAS G12C mutants does not mean that the road to the development of KRAS targeted anti-cancer therapies is "unblocked.
"
This is because the KRAS gene mutation is called carcinogenic mutation because the mutation makes KRAS in an activated state combined with GTP.
This continuous activation state promotes the production and proliferation of cancer cells.

Then the question arises.
Compounds targeting KRAS G12C can only bind to KRAS G12C mutants that are in an inactive state.
Can it affect the activated KRAS mutants in the patient's cancer cells? Image source: Reference [7] In 2016, the research team of Araxes Pharma answered this question.

In a paper published on Cancer Discovery, researchers found that although the KRAS G12C mutant is called an activating mutation, the mutant itself is not permanently activated by binding to GTP.

It will still switch rapidly between the activated state combined with GTP and the inactivated state combined with GDP, but the genetic mutation makes the KRAS mutant more likely to be in the activated state.

This discovery provides a "window" for covalent inhibitors that only bind to KRAS G12C mutants in the inactive state to affect the KRAS mutants in the activated state, as long as they bind to them when the KRAS mutant is converted to the inactive state, it will be able to KRAS is "locked" in an inactive state, so that all KRAS in the cell is gradually transformed into an inactive form.

This research result breaks the traditional concept that the G12C mutant is in a continuously activated state, and provides important evidence for the therapeutic potential of covalent inhibitors targeting KRAS G12C.

▲The rapid transition of the KRAS G12C mutant between the activated state combined with GTP and the inactivated state combined with GDP provides a covalent inhibitor with an opportunity to exert a therapeutic effect (picture source: reference [7]) and covalent The advancement of covalent inhibitors technology has also given researchers the ability to find more effective KRAS G12C inhibitors.

The covalent inhibitor can produce a covalent chemical bond after binding to the target, thereby irreversibly inhibiting the activity of the target.

Previously, the development of covalent inhibitors was often based on the modification of non-covalent inhibitors.

Drug developers first find non-covalent inhibitors that can bind to biological targets, and then add chemical groups that can create covalent bonds with the target on their backbone.

The development of the KRAS G12C covalent inhibitor represents a change in the concept of covalent inhibitor development.

The researchers directly screened candidate small molecule compounds that can form a covalent bond with the cysteine ​​on the mutant.

Although this screening method did not find a compound that can bind to the mutant with high affinity, it found a compound that can quickly form a covalent bond with cysteine.

"Hurry up" and deliver innovative therapies to patients.
After Professor Shokat revealed the crystal structure of the KRAS mutant's new combination of "pocket" in the journal Nature, many biomedical companies invested in drug research and development along this direction.
.

Among them, Amgen also discovered candidate small molecule inhibitors targeting KRAS G12C through high-throughput screening of the compound library.

Generally, drug development is a long process, and the time required for a drug from the initial discovery of the lead compound to the final approval is often more than ten years.

However, thanks to the efforts of R&D staff, after the publication of the 2013 "Nature" paper, Amgen’s candidate KRAS G12C inhibitor AMG 510 announced its first clinical trial results in 2019.
Five patients with lung cancer received partial remission.

Subsequently, Amgen quickly launched the key phase 2 clinical trial CodeBreaK 100, and the US FDA also granted AMG 510 breakthrough therapy designation and priority review qualifications, further accelerating the development of this innovative therapy.

The time for the FDA to accelerate the approval of Lumakras is also close to 3 months earlier than the scheduled response time.
The development and review process of the "fast-track" development and review process allows this innovative treatment to be delivered to patients as soon as possible.

▲The molecular structure of Lumakras (picture source: Edgar181, Public domain, via Wikimedia Commons) The future of KRAS targeted therapy Lumakras' approval by the FDA is undoubtedly an important milestone in overcoming the "undrugability" of KRAS.

In addition to Lumakras, many KRAS-targeted research therapies have entered the clinical development stage.
Among them, adagrasib (MRTX849) developed by Mirati Therapeutics is expected to submit a new drug application to the FDA in the second half of this year.

However, the development of targeted therapy for KRAS still faces many challenges.

For example, although Lumakras has shown positive effects in the treatment of patients with non-small cell lung cancer, its effect in the treatment of patients with colon cancer is not significant.

Moreover, current research has found that patients treated with Lumakras in clinical trials can develop KRAS mutations that are resistant to Lumakras, thereby rendering Lumakras ineffective.

In addition to KRAS G12C, KRAS also has many other mutation types, and Lumakras has no effect on other mutation types.

Talking about the future of KRAS targeted therapy development, Dr.
Liu Yi, co-founder of Araxes Pharma, said in an interview with WuXi AppTec's content team that the problem of resistance to KRAS inhibitors and different efficacy in different cancer types is not the same.
It is not the unique challenges faced by KRAS targeted therapies.
These challenges exist in the development of all targeted therapies.

The drug research and development industry also has relatively mature solutions to these challenges.

For example, combination therapy will become one of the important research directions to overcome drug resistance mutations and expand the scope of application of KRAS inhibitors.

At present, Amgen has carried out more than ten clinical trials to test the efficacy of Lumakras and SHP2 targeted therapies, immune checkpoint inhibitors, and other targeted therapies in combination.

The company also published a study in the journal Nature, expounding the research and development direction of KRAS inhibitor combination therapy.

In addition to targeting KRAS G12C mutants, other drug development methods are also expected to achieve breakthroughs.

For example, Revolution Medicines has been honed for nearly 10 years in developing inhibitors that combine with the activation state of KRAS.

Although the KRAS protein itself lacks a "pocket" that binds to small molecule drugs, Revolution Medicines’ technology platform takes a different approach.
The small molecule inhibitor developed can form a trimer with KRAS protein and another chaperone protein, allowing the chaperone protein and KRAS protein to form a trimer.
The protein unites to form a "pocket" that binds to small molecule drugs.

Protein degradation therapies targeting KRAS and innovative therapies that target mRNA to inhibit KRAS expression may also have effects on a variety of KRAS mutants.

"In the past ten years, it has been the most exciting and gratifying thing for developers to witness the targeting of KRAS G12C mutants starting from the initial concept and finally becoming an innovative drug that saves the lives of patients.

" Dr.
Liu Yi said.

We expect that with this breakthrough, more R&D strategies targeting KRAS can be transformed into new drugs and good drugs as soon as possible, which will benefit the majority of cancer patients.

Reference materials: [1] Ostrem et al.
, (2013).
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.
Nature, https://doi.
org/10.
1038/nature12796[2] Rudolph et al.
, (2021).
Emerging Trends in Cancer Drug Discovery—From Drugging the “Undruggable” to Overcoming Resistance.
Cancer Discovery, DOI: 10.
1158/2159-8290.
CD-21-0260[3] How a protein'Polaroid' led Amgen to finally crack the'Achilles heel tumor' with Lumakras in 8 years.
Retrieved May 29, 2021, from https:// -cancer-breakthrough-lumakras-8-years[4] KRAS Information Center.
Retrieved May 29, 2021, from https:// Revolution Medicines.
Retrieved May 30, 2021, from https: // Araxes Pharma Enters Into Cancer Drug Discovery and Development Agreement With Janssen Biotech.
Retrieved May 30, 2021, from https:// -into-cancer-drug-discovery-and-development-agreement-with-janssen-biotech-193530441.
html[7] Patricelli et al.
, (2016).
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.
Cancer Discovery, DOI: 10.
1158/2159-8290.
CD-15-1105.
Note: This article aims to introduce the progress of medical and health research, not a treatment plan recommendation.
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.
Cancer Discovery, DOI: 10.
1158/2159-8290.
CD-15-1105.
Note: This article aims to introduce the progress of medical and health research, not a treatment plan recommendation.
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.
Cancer Discovery, DOI: 10.
1158/2159-8290.
CD-15-1105.
Note: This article aims to introduce the progress of medical and health research, not a treatment plan recommendation.

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