The strength target KRAS G12D: the unpreparable medicine is encircled and suppressed again

Author: Leaf

RAS is the first oncogene identified in human tumors, and it is also one of the most widespread oncogenic mutation genes

The currently known members of the RAS gene family include KRAS, NRAS and HRAS

One "point" is different, two sorrows and joys

The KRAS protein is encoded by the Kirsten rat sarcoma virus oncogene homolog (KARS) and belongs to the small GTPase (smallGTPase) containing 188 amino acids

By responding to extracellular signals, the KRAS protein cyclically switches between the activated state (ON) that binds to GTP and the inactive state (OFF) that binds to GDP, maintaining normal biological functions

Nat Rev Drug Discov.

Due to the high affinity of mutant KRAS to guanosine triphosphate (GTP), and the existence of small catalytic sites, smooth protein surface and other factors that are difficult to target, the development of small molecule inhibitors has always been challenged, resulting in KRAS The legend of "unable to medicine"

However, the scientists did not retreat

Compared with KRAS G12C, KRAS G12D only differs in amino acid mutations on the same codon

Cell Rep Med.

KRAS has the highest incidence of pancreatic cancer, and pancreatic cancer is also commonly known as "the king of cancer", and its treatment options are limited

Mirati Therapeutics (the same below)

Secondly, this "point" between KRAS G12D and KRAS G12C is different, which directly leads to the fact that KRAS G12C inhibitor drugs cannot be directly used to treat KRAS G12D mutant tumors.

It is precisely this "point" difference and connection between KRAS G12C and KRAS G12D.

Note: The company only lists the global and Chinese rights holders

MRTX1133: The first KRAS G12D inhibitor to publish preclinical data

MRTX1133 is a selective non-covalent KRAS G12D inhibitor obtained by MiratiTherapeutics on the basis of Adagrasib, using pyrido[4,3-d]pyrimidine backbone to further screen and optimize.

In summary, Mirati screened the substitution groups at the 2, 4, and 7 positions of pyrido[4,3-d]pyrimidine to improve activity and selectivity

The optimization of the three substitution positions of the pyrido[4,3-d]pyrimidine skeleton improves the overall binding activity and selectivity of MRTX1133

In the in vitro model, MRTX1133 also showed highly effective inhibitory activity and powerful anti-tumor effects

Domestic enterprises: who will encircle KRAS G12D

At present, domestic companies only publicly announced the development of KRAS G12D inhibitor (JAB-22000)
.
However, according to the development ideas of Mirati's KRAS G12D inhibitor MRTX1133 and Amgen's patent layout, domestic KRAS G12C inhibitor development companies also have the opportunity to fight to encircle KRAS G12D.
Gakus is an example
.

Of course, it remains to be seen whether domestic companies that already have experience in the development of KRAS G12C inhibitors will participate in the encirclement and suppression of KRAS G12D
.
It is reported that domestic companies have recently submitted IND applications for KRAS G12D inhibitors, indicating that the battle of domestic companies to encircle and suppress KRAS G12D may officially begin
.

Note: Only statistics of domestic company information

In addition, using "KRAS G12C inhibitor" searched by Scifinder, 33 domestic companies or institutions (excluding subordinate subsidiaries and branches) respectively submitted 72 patent applications in the field of KRAS G12C
.
However, the current domestic patent layout of KRAS G12D is mainly in the field of testing and modelling, and there is no publication of patents for small molecule KRAS G12D inhibitors applied by domestic enterprises or individuals
.

However, compared to whether to participate in the KRAS G12D encirclement and suppression, domestic companies may be more important to consider how to build their own advantages and barriers to avoid becoming the target of the "encirclement and suppression" while encircling KRAS G12D
.
When drugs of the same mechanism have achieved 2 to 3 clinical uses, followers will face small spaces and huge competition.
Therefore, the clinical advantages and differences of drugs will be crucial, and how to achieve such barriers requires in-depth exploration by various companies.

.

references:

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2020Aug;19(8):533-552

[2]The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer(NSCLC).
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2021 Jan 19;2(1):100186

[3]Targeting KRAS: The Elephant in the Room of Epithelial Cancers.
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[4]KRAS G12C Mutations in NSCLC: From Target to Resistance.
Cancers 2021, 13, 2541

[5]https:// mutant lung cancer: progress thus far on an elusive therapeutic target.
Clin Trans Med (2015) 4:35