"Unable to be a drug" target finally becomes history KRAS inhibitor breakout contest kicks off

Author: Duxing

Recently, Cinda Biotech and Jinfang Pharmaceutical reached a licensing agreement to obtain the latter's exclusive global development and commercialization rights for the KRAS G12C inhibitor GFH925 in China (including Mainland China, Hong Kong, Macau and Taiwan), and has global development and commercialization The right to choose rights

KRAS was once considered a "non-drugable target", but Amgen's AMG510 was approved for marketing in May 2021, breaking the curse of "non-drugging" and providing a new drug option for patients with KRAS mutations

Overview of R&D progress of some KRAS around the world

Data source: Yaozhi data, corporate announcements and other public information

(1) Overview of KRAS targets

RAS (rat sarcoma) is a low-molecular-weight (21kDa) guanine nucleotide binding protein with GTPase activity located on the cell membrane, including three subtypes of HRAS, NRAS and KRAS

In healthy cells, the cycle of RAS binding to GDP/GTP is very slow

Figure: RAS switch icon

Data source "Targeting the untargetable KRAS in cancer therapy"

For the RAS mutation, the hydrolysis of GTP is the key to the binary switch

In view of this, scientists set their sights on the KRAS gene

Figure: KRAS activation and inactivation

Data source "Specific functions of Kras in cancer initiation"

Aiming at the bottleneck of the lack of binding pockets on the KRAS protein surface, the "tethering" technology finally broke the ground

(2) Global layout of KRAS G12C inhibitors

(1) AMG510 is the first oral inhibitor targeting KRAS G12C approved for marketing.

Picture: AMG510

Data source Amgen

In May 2021, Amgen's AMG510 (Sotorasib) was approved by the FDA for marketing, breaking the curse of KRAS "not a drug", and its indication is the second-line treatment of non-small cell lung cancer with KRAS G12C mutation

On 2020ASCO, Amgen announced the Phase I clinical data of AMG510 for the treatment of colorectal cancer (CRC).

(2) MRTX-849 (Adagrasib) is designed by Mirati Therapeutics, and its structure is similar to Amgen's AM510

Figure: MRTX-849 chemical structure

Data source: Mirati Therapeutics

In the phase I/II trial code-named Krystal-1, MRTX-849 showed good anti-tumor activity and tolerable safety in a variety of tumors with KRAS G12C mutations

In addition to monotherapy, MRTX-849 is exploring a combination program with drugs such as pembrolizumab or cetuximab

Figure: MRTX-849 mechanism of action

Data source: Mirati Therapeutics

(3) Eli Lilly entered the research and development of KRAS G12C inhibitors earlier, but the first KRAS G12C inhibitor LY3499446 was suspended in phase I clinical trials in 2020 due to toxicity issues

(3) Domestic KRAS G12C inhibitor layout

According to statistics, so far, a total of 10 KRAS inhibitors have been declared clinically in China, of which 3 are imported and 7 are domestically produced

Image source: China Sea Securities

BPI-421286 from Betta Pharmaceuticals is a new type of potent and highly selective covalent irreversible KRAS G12C oral small molecule inhibitor

Yifang Bio's D-1553 is the first KRAS G12C inhibitor independently developed and entered clinical trials in China.
It has launched international multi-center phase I/II clinical trials in the United States, Australia, China and other countries, and will start domestically in April 2021.
Approved clinically
.
Pre-clinical trials have shown that, compared with similar drugs under investigation, D-1553 has higher bioavailability and lower plasma protein binding rate
.

Jacos is currently developing three KRAS inhibitor projects, namely JAB-21822, JAB-22000 and JAB-23000, which are used to inhibit G12C, G12D and G12V mutant KRAS
.
In pre-clinical trials, JAB-21822 showed superior PK characteristics than AMG 510 and MRTX-849 and affinity for KRAS G12C, and has good therapeutic potential
.
On August 3, 2021, the clinical trial of JAB-21822 completed the first patient administration in China
.
In addition, the company is also exploring the therapeutic effects of the combination of KRAS inhibitors and SHP2 inhibitors
.

(4) Summary

In view of the structural characteristics of KRAS mutants, the complexity of signal pathways, and the drug resistance of KRAS mutant tumors, KRAS was once known as the "non-drug target"
.
Amgen’s AMG-510 breaks the curse that KRAS mutations are incurable and provides a brand new medication option for patients with KRAS mutations
.
There are also a number of domestic pharmaceutical companies that are deeply engaged in the KRAS G12C target.
Yifang Bio and Betta Pharmaceuticals are currently in the leading R&D progress and are both in clinical phase I, while more than ten companies such as Jiaxi, Jinfang Pharmaceutical, and First Pharmaceutical Holdings, etc.
In the pre-clinical stage, we continue to improve and strive to accelerate the development of clinical trials of related drugs
.
Of course, KRAS G12C is not a perfect answer.
After all, the problem of resistance always exists, but scientists are also working to improve, such as exploring the combination of KRAS inhibitors and SHP2 inhibitors
.
How this target will develop in the future, and who will stand out, let us wait and see
.