What breakthroughs are behind the 40 years of sharpening the sword and conquering the famous "unable to medicine" target

KRAS gene mutation is one of the earliest oncogene mutations discovered, and it is also the most common oncogene mutation in human cancer.

KRAS’s “unpreparable” nature was finally breached last week.

Revealing 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 be one of the breakthrough studies that changed the direction of therapy development.

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.

Development of KRAS G12C covalent inhibitor

However, the discovery of a pocket capable of binding to the KRAS G12C mutant does not mean that the road to the development of KRAS-targeted anti-cancer therapies is "unobstructed.

In 2016, the research team of Araxes Pharma answered this question.

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.

▲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])

The advancement of covalent inhibitors technology also gives researchers the ability to find more effective KRAS G12C inhibitors.

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

"Hurry up" and deliver innovative therapies to patients

After Professor Shokat revealed the crystal structure of the KRAS mutant's new binding "pocket" in the journal Nature, a number of biomedical companies have invested in drug research and development along this direction.

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.

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.

▲Lumakras molecular structure (picture source: Edgar181, Public domain, via Wikimedia Commons)

The future of KRAS targeted therapy

The approval of Lumakras by the FDA is undoubtedly an important milestone in overcoming KRAS's "non-drugability".

Talking about the future of KRAS targeted therapy development, Dr.

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

Note: The original text has been deleted

Reference materials:

[1] Ostrem et al.

[2] Rudolph et al.
, (2021).
Emerging Trends in Cancer Drug Discovery—From Drugging the “Undruggable” to Overcoming Resistance.
Cancer Discovery, DOI: 10.
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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:// -polaroid-led-amgen-to-cusp-a-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:// 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.