Are Covalent Bonds Strong? Covalent Drugs Acting On Epigenetics - Menin Inhibitors

Covalent drugs have been developed for more than 100years, dating back to aspirin in 1899. Have you ever considered are covalent bonds strong? The major difference between covalent and non-covalent drugs isthat covalent drugs can permanently "turn off" target proteins byforming covalent bonds with them, while non-covalent drugs cannot completely"turn off" target proteins because the binding process with them isreversible. The binding process of non-covalent drugs to target proteins isreversible and thus cannot completely "turn off" the target protein.Therefore, although covalent drugs have a history of more than 100 years ofdevelopment, it is only in the past 10 years that they have gained recognitionand ushered in a period of rapid development, due in large part to thedevelopment of proteomics, which has prevented the majority of off-targeteffects at the cognitive level. the vast majority of off-target effects,allowing covalent drugs to have sufficient evidence to advance toward theclinic.

Scientists explore are covalent bonds strong. In addition to the approved ones mentioned above, there are also KRASG12C inhibitors currently in development, such as AMG510 and MRTX849, which isa substitution of glycine for cysteine at amino acid 12 of the peptide chain, amutation that is only present in cancer cells and does not affect conventionalKRAS. It has been found that KRAS G12C requires a nearby lysine to assist indragging in order for the small molecule to successfully meet the G12C cysteineand form a covalent bond, a similar strategy does not work for KRAS G13C, whichis mutated one amino acid further away than G12C, probably because it is toofar from the lysine responsible for dragging. In contrast, KRAS G12C inhibitorsthat enter the clinic do not have a strong affinity, but can react rapidly toform covalent bonds whenever they meet by chance.

Epigenetics, originally proposed by ConradWaddington in the 1950s, refers to stable heritable phenotypes that result fromchanges in chromatin but not in DNA sequence. Epigenetics can be divided intothree applications, namely DNA methylation, histone modification, andnon-coding RNA regulation. To date, the FDA has approved seven drugs based onepigenetics for the treatment of cancer, two DNMT inhibitors (azacitidine anddecitabine) and five HDAC inhibitors (vorinostat, romidepsin, belisostat,pabister, and cidabendiamide). Some experiments verify are covalent bondsstrong.

Methylation of histone third subunit IVlysine (H3K4me) is a specific histone lysine methyltransferase (HMT) that iscatalyzed primarily by the MLL protein family (also known as the KMT2 proteinfamily), while menin binds highly specifically to wild-type MLL1/2 and MLL1fusion proteins to regulate downstream MEIS1, HOXA9, and DMNT3A Menin-MLLbinding has been associated with leukemia, with MLL-r, NPM1 mutant and othersubtypes strongly associated with it, and thus the development of drugs thatblock Menin-MLL binding has the potential to be effective in leukemia. So, arecovalent bonds strong?

A total of three menin inhibitors arecurrently in the clinical stage, except for Daiichi Sankyo's DS-1594b for whichinformation is not yet disclosed, the other two are non-covalent drugs, andthus Biomea fusion's BMF-219 covalent drug is competitive.

The recently published clinical data ofmenin inhibitor, the ORR of 48% in terms of effectiveness is still good, amongwhich the MRD negative reaches 67%. But the biggest problem is QT intervalprolongation, in each grade of AE, the proportion of QT interval prolongationAE is on the rise, in grade 3 AE, 60% of them are due to QT intervalprolongation, which means that QT interval prolongation is the main driver ofhigh grade AE. The day this data was released, Syndax's share price fell 30% inresponse.

So is the same problem true for other menininhibitors in development? For the time being, we should be cautious about thepotentially more potent and potentially more off-target toxic drug BMF-219,until the mechanism of QT interval prolongation is understood or more clinicaldata are published for other menin inhibitors.

If BMF-219 is developed successfully,according to the estimated population data given by Biomea fusion, theMLL-R/NPM1 population penetration rate is taken as 50%, the rest penetrationrate is taken as 20%, and the annual cost is referenced to $148,000 foribrutinib, then the peak of the U.S. market is about $4,491.8 million, which isalso a potentially heavy drug close to ibrutinib, but of course, at present Thefirst obstacle lies in the QT interval prolongation.

Erucitinib initially attracted attention inpart because a large portion of the pharmaceutical community was discouragedbased on its non-selective structure, but subsequent events have forced them toreevaluate their thinking. We will have to wait and see if the menin inhibitorwill undergo such a reversal.