Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors

Background

The discovery of potent, selective, and orally available inhibitors of the IRE1α enzyme is a significant development in the treatment of multiple myeloma, a type of cancer that affects plasma cells in the bone marrow. The IRE1α enzyme plays a crucial role in the unfolded protein response pathway, which is activated in response to cellular stress and plays a role in the survival and proliferation of cancer cells. Inhibition of IRE1α has been shown to inhibit the growth of multiple myeloma cells and enhance the efficacy of existing treatments.

Introductions

Amgen reported compounds 16 and 18 as potent selective variant inhibitors of the kinase IRE1α, but unfortunately, this class of structures did not show significant cellular activity. Recently, however, Genentech published an important article in the journal JMC using this class of structures as lead molecules. Improving the physicochemical properties of the compounds by reducing lipophilicity, molecular weight and basicity led to the discovery of a series of novel compounds with good in vitro safety and good oral exposure. A potent and selective compound in vivo, G-5758, was finally identified, which was well tolerated after oral administration of up to 500 mg/Kg for multiple consecutive days. In a multiple myeloma model (KMS-11), G-5758 was comparable to the pharmacodynamic effect of inducing IRE1 knockdown as measured by XBP1s levels.

Method and Disscussions

The researcher first explored the piperidine in the solvent exposed region by performing ring reduction, ring opening or introducing polar groups, but this rather reduced the affinity of the structure, so the piperidine ring was retained and the phenylsulphonamide was modified to open the protein-ligand complex in SeeSAR and it was seen that there was still some unoccupied space around the phenyl group and a large hydrophobic region, so attempts were made to make an extension of the benzene ring or to replaced with a chain or aliphatic ring. Interestingly, the aliphatic ring instead reduced the affinity, and fragment growth was performed using FastGrow in the inspirator module to further increase the affinity to obtain compound 15.

Subsequently, in order to reduce the lipophilicity to mitigate the off-target activity, the focus was on the replacement of the naphthalene ring and the introduction of the fluorine atom, and the replacement can then be done using ReCore, but the pharmacophore restriction needs to be done here to get the compound 26, and subsequently, in order to further enhance the passive penetration, the piperidine was again structurally modified, and this step can be done using the inspirator module in the Medchemesis implementation, where only minor structural or elemental changes are made to alter the pharmacophore properties while maintaining high affinity. Compound 29 (G-5758) obtained by introducing a fluorine atom at the 5-position of the piperidine ring showed an even better passive diffusion ability.

Conclusions

The researchers found that the newly discovered IRE1α inhibitors were potent, selective, and orally available, and demonstrated comparable pharmacodynamic modulation to the genetic knockdown of IRE1 in a multiple myeloma model. This suggests that these inhibitors could be effective in inhibiting the growth of multiple myeloma cells by targeting the IRE1α enzyme. The development of these inhibitors could lead to the development of novel treatment strategies for multiple myeloma and other cancers that rely on the unfolded protein response pathway for survival.

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