Can different routes go the same way?

Author: Shencheng Hu Ge

The protein arginine methyltransferase PRMT5 plays an important role in maintaining cell homeostasis.

In view of the important role of PRMT5 in normal tissue homeostasis, PRMT5 inhibition may have a limited therapeutic window, and there is currently no molecule on the market for this target

Merck's dual suppression strategy

In 2021, Merck reported in JMC magazine a class of 5,5-bicyclic nucleoside PRMT5 inhibitors for the treatment of cancer; activated PRMT5 and aptamer MEP50 form a heterooctamer, and use S-gland Glycosylmethionine (SAM) acts as a cofactor to transfer the methyl group to the substrate arginine (see Figure 1);

Figure 1 Combination mode of SAM (green, PDB 4X61) and PRMT5, the yellow dotted line shows the main effect

The active site of the enzyme consists of a conserved SAM binding pocket and a nearby protein substrate binding pocket.

In Figure 1, the diol in the SAM structure forms hydrogen bonds with Tyr324 and Glu392, the purine C6-amino group is hydrogen bonded with Asp419, and the purine N1-nitrogen hydrogen bond forms a hydrogen bond with the main chain amide-NH of Met420

Merck's compound design aims to develop new nucleosides and substituents that can interact with glu444

Figure 2 (A) Designed 5,5 bicyclic skeleton by fusion of 3'and 4'; (B) several key nucleoside binding pharmacophores of 4

Figure 3 SAR of 5, 5-bicyclic ribose

5, 5-Bicyclic ribose SAR discussion: Merck mainly investigated the structure-activity relationship of bicyclic ribose when oxygen and methylene are used as the linking chain, and replaced the NH2 of purine with methyl, cyclopropyl, and H groups.

However, the PK and solubility tests of the C6 amino substitution series show (Figure 4) that the rat bioavailability of compounds 4 and 29~33 is relatively poor, and the better compound 33 is only 28%; when the oxygen atom is a linking chain, The solubility is poor, and when the ortho position of the aminoquinoline is F substituted and the methylene group is used as the bicyclic linker, the solubility is greatly improved

Figure 4 PK and solubility of C6 -amino base analogues

In the C6-methyl base substitution series (Figure 5), the bioavailability of rats has been greatly improved, and the bioavailability of compound 35 has increased to 71%

Figure 5 PK and solubility of C6-methyl base analogues

The current modification has not yet obtained a compound with high affinity, good PK (high F% and long MRT> 2h), suitable solubility (≥50 μM) and low risk of CYP3A4 mediated DDI (drug-drug interaction)

Figure 6 lists the data of some all-carbon 5,5 bicyclic analogs.

Figure 6 PK and solubility of all-carbon 5,5-bicyclic analogues

Comprehensive considerations, single-digit nanomolar activity, high F%, excellent solubility, and suitable PK make this all-carbon bicyclic ring a more promising framework

Figure 7 Human dose prediction of all-carbon bicyclic PRMT5 inhibitor (Compound 72)

Merck finally discovered compound 72, a bicyclic nucleoside analog with good PK, high solubility, low DDI risk and low predicted human dose.

Merck's related patent layout

Search for keywords of PRMT5 in the database of the European Patent Office, query Merck’s patents on PRMT5 inhibitors, and find 10 compound patents and one Biomarker related patent (Table 1).

Merck's PRMT5 inhibitor related patents

The compound 1b in patent WO2021126731 is modified according to GSK-3326595 (in phase II clinical).

Summary and outlook

The synthetic lethal inhibitors of Amgen (AMG193) and Mirati (MRTX1719) are also expected directions.

From this point of view, the two strategies have reached the same goal by different routes

Note: The original text has been deleted

references:

[1]Michelle R.
Machacek etal; The Discovery of Two Novel Classes of 5,5-Bicyclic NucleosideDerived PRMT5 Inhibitors for the Treatment of Cancer; J.
Med.
Chem.
2021, 64, 3911−3939;

[2]Alessandra Ianari etal; Discovery of a First-in-Class Inhibitor of the PRMT5−Substrate Adaptor Interaction; J.
Med.
Chem.
2021, 64, 11148−11168;

[3] Merck & Co; PRMT5 inhibitor; CN112805006 A;

[4] European Patent Office database;

[5] https://clinicaltrials.
gov/ct2/home
.

[6] Medical Rubik's Cube Database;

[7]AACR-NCI-EORTC 2021: MRTX1719: A First-in-class MTA-cooperative PRMT5 Inhibitor that Selectively Elicits Antitumor Activity in MTAP/CDKN2A Deleted Cancer Models;