"Spy" on the KRAS G12C patents of major companies

The "popular fried chicken" recently developed by new drugs is none other than KRAS
.

After decades of research, with the successful launch of two KRAS G12C inhibitors AMG510 (Amgen) and MRTX849 (Mirati) (Figure 1), the "non-druggable" target of KRAS mutant genes officially came to an end

Needless to say, the importance of KRAS in the field of tumor treatment
.

This article starts with many KRAS G12C patents, and selects some interesting structures to explore the design concepts of different companies

01

01

AstraZeneca

AstraZeneca

WO2019110751A1

WO2019110751A1

From the general formula (left of Figure 2), the main design idea of ​​AZ is to connect the piperazine ring with the core to form a four-ring system (right of Figure 2)
.

The research and development team found that the active conformation of 4-piperazinoquinazoline is about 312o, and the lowest energy conformation of the Hit molecule is 60o, 150o ~ 210o and 300o respectively

WO2018206539A1

This AZ patent also uses the above-mentioned similar design concept, but the direction of the loop is different (Figure 3)
.

02

02

Eli Lilly

Eli Lilly

WO2020081282A1

WO2020081282A1

Eli Lilly’s patent core is actually not too novel, but it creatively developed a fragment such as benzothiazolamide to replace the original pharmacophore fluorophenol (Figure 4)
.

Among them, the representative compound 1 not only has nanomolar-level in vitro activity, but also exhibits excellent anti-tumor activity in vivo

WO2021118877A1

Eli Lilly's recently published patent structure (Figure 5) is very similar to AZ's WO2018206539A1
.

The author speculates that it may be a series of new active structures derived from Lilly's own development based on the concept of AZ (Figure 5)

03

03

Incyte

Incyte

WO2021142252A1

WO2021142252A1

Incyte's R&D and design ideas are similar to those of AZ
.

The difference is that AZ connects the piperazine ring to the nucleus to form a four-ring system, while Incyte builds a triple-ring system through the N atom (Figure 6)

04

04

MSD

MSD

WO2021086833A1

WO2021086833A1

Merck’s patent strategy is very clear: on the basis of AMG510, the aromatic ring below the core and the aromatic ring on the left side of the core are connected to form a large ring through a flexible linker (Figure 7)
.

This modification not only successfully broke through Amgen's patent, but also found some compounds with good activity, some of which reached the nanomolar level

05

05

Novartis

Novartis

WO2021120890A1

WO2021120890A1

Novartis' clinical compound JDQ44 is derived from this patent
.

By analyzing the structure of the patented compound, the author believes that JDQ44 may be a skeleton transition based on the topological shape of AMG510 (Figure 8)

06

06

Hausen

Hausen

WO2020239077A1

WO2020239077A1

Hausen is a domestic pharmaceutical company that deployed KRAS very early, and has also applied for multiple KRAS patents
.
Looking at the entire patent, you can find that it contains many different structural types of KRAS inhibitors, and some compounds overlap with other company patents
.
Due to space reasons, this article selects the most important compound 165-1 in the patent for a brief description (Figure 9)
.

Example 165-1 basically retains the skeleton structure of AMG510.
The biggest difference is that S methyl ether at the 4-position of pyridine replaces the methyl group at the same position of AMG510
.
From the in vitro activity point of view, the IC50 of Example 165-1 against NCI-H358 and Mia PaCa-2 cell lines are 6.
6 nM and 3.
3 nM, respectively, which is equivalent to AMG510
.
In the NCI-H358 model of human lung cancer with KRAS-G12C mutation, 165-1 can significantly inhibit tumor growth at 10 mg/kg QD, which is better than AMG510 at the same dose (Figure 10)
.
Moreover, the compound's plasma stability, tumor/plasma exposure, etc.
are better than AMG510, and hERG, DDI and other safety risks are small
.
Many parameter blessings make people wonder whether 165-1 is Hausen’s PCC compound?

WO2020239123A1

The scope of protection of this patent of Howson is also very broad, and there are many structural types of compounds
.
However, the author found that there are two types of core structures that are very similar to the two patent ideas of AZ (Figure 11): directly use the AZ design strategy on the basis of the AMG510 skeleton
.
Although the specific activity data of the representative compound has not been given, it is expected that it should have very good potential
.

07

07

Jinfang Medicine

Jinfang Medicine

WO2020221239

WO2020221239

Jinfang Medicine is also a domestic company that followed up with KRAS very early
.
From the general formula and representative compounds of this patent, it can be seen that Jinfang also borrowed from the design concept of AZ (Figure 12): the use of AZ's ring formation strategy (same as Hausen) on the AMG510 skeleton
.
The compound activity data given in the patent is also very eye-catching.
The IC50 of many compounds has reached the nanomolar level, some of which are even less than 1 nM
.
However, compared with the above-mentioned Hausen patents, some patented compounds have a very high degree of overlap.
I don't know who will get the final patent authorization
.

WO2021083167A1

This patent of Jinfang Medicine also draws on AZ (Figure 13): the design concept of using AZ's lactam four-membered ring directly on the AMG510 skeleton
.
Compared with the previous patent, this patent has done a very in-depth study in vivo and in vitro
.
Among them, the representative compounds Z25-2 and Z27-2 showed comparable inhibitory activity to AMG510 against NCI-H358 and Mia PaCa-2 cell lines, and were significantly better than AMG510 in both in vivo evaluations of PK and PD (Figure 14) , Showing the potential of Me better
.
However, the same problem remains.
This patent seems to overlap with Howson's patent
.
Not only that, this patent of Jinfang Medicine also overlaps with CN112300194A (Shanghai Lingda Biomedical Co.
, Ltd.
), and Z27-2 is extremely "similar" to Example 7 among them
.
I don't know how these three companies evaluated these patent crashes
.

At present, research on new drugs for KRAS at home and abroad is in full swing, and the track is relatively crowded
.
In the process of investigating patents, the author also found that serious homogeneity competition and frequent patent crashes caused a huge waste of R&D resources and clinical resources
.
If pharmaceutical companies cannot formulate effective R&D strategies based on their own advantages, they will face fierce competition in the future
.

references:

Hao Chen et al.
Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics.
Journal of Medicinal Chemistry 2020 63 (23), 14404-14424