AstraZeneca Discloses an Information-Driven Series of Cbl-b Inhibitors with Optimized Metabolic Stability and Cellular Potency

Jan 28, 2024 21:38 CST Updated 21:38

AstraZeneca

Biopharmaceutical Manufacturer

AstraZeneca recently reported a novel class of Cbl-b inhibitors identified through HTS screening.

Recently, they reported another information-driven series, as shown in the figure below.

Nurix's follow-up molecules may be first-in-class in this target, and aside from AstraZeneca, several other prominent companies are also following (see figure below). In China, BeiGene and Simcere Zaiming have also made strategic investments in this target.

So here we can demystify a bit: large foreign companies or star biotechs don't avoid doing fast-follow (in fact, many do), they just also have the ability to pursue FIC (First-in-Class). Regarding AstraZeneca's two series of Cbl-b, from a discovery perspective, the HTS-screened series is certainly more novel and interesting. However, from a practical standpoint, it’s uncertain which series will ultimately succeed. In fact, neither of the two articles published by AstraZeneca mentioned moving forward to a clinical candidate, so it’s possible neither will be advanced.Moreover, different people have different understandings of first-in-class, and the molecules screened by AstraZeneca themselves.ActuallyIt's not exactly FIC either, but that's going off-topic. Whether it's FIC or not, what matters most is its value.

Of course, fast-follow returnsFast-follow also has different levels.Still need to make a differentiation(Unless they can move particularly fast). In their case, one point mentioned in the article is about improving metabolism. For the Nurix molecule, they identified the piperidine moiety of molecule 1 as the primary metabolic site through Met ID. Hence, the goal was to create structurally distinct molecules while maintaining...Other major interactions of Nurix molecules, while replacing piperidine.

Molecular design is structure-based design. They first analyzed the co-crystal structure of Nurix molecule 1, clarified the binding mode, and based on this, designed a series of molecules. After FEP calculations, the following molecules 8 and 9 (and possibly others) were selected for synthesis and testing, followed by the analysis of the co-crystal.

The binding modes and biochemical activities of molecules 8 and 9 are shown in the figure below (the cyan molecule is Nurix molecule 1). Molecules 8 and 9 show acceptable activity, but there is no direct comparison with Nurix molecule 1. Additionally, there are two interesting points in the data below: the matched pair of molecules 9 and 10. The decreased activity of molecule 10 may be due to the lack of a water bridge HB, but could there be other reasons? Molecule 10 has a smaller polar surface area, yet its logD is a whole unit lower—why is that? If interested, one might consider this and try using available logD/P prediction software.

Based on the above results, molecule 9 was selected for further modification and optimization. MD simulation analysis of its co-crystal structure revealed that the water bridge hydrogen bond observed in the co-crystal structure might not be very important, and substitution at the pyridone NH could be attempted.

The results are shown in the two charts below. Methylation at NH leads to a slight decrease in activity. Further optimization of the substituents improves activity; by the time of compound 31, cellular activity reaches the best in the series as reported in the article. Additionally, the article mentions that compared to compound 27, compound 31 shows similar biochemical activity, but...Cell activity is much better, and the article attributes this to differences in the activity of cCbl (Cbl-b homologous protein).

The co-crystal structure of molecules 30 and 31 is as follows.

Additionally, by observing the co-crystal structure of molecule 9 and molecule 31, it can be found that to perform a substitution at the pyridone NH (while maintaining or enhancing activity), not only does the water involved in the water bridge hydrogen bond need to be displaceable, but also minor conformational changes of the surrounding protein residues are required to accommodate the substitution. Details are shown in the figure below.

Finally, the functional effect potency of molecules 30 and 31 was compared with that of Nurix molecule 1.

The figure below shows the results of the preferred molecules from AstraZeneca's previously reported novel scaffold series. Although not from the same paper as the figure above, it originates from the same company and assay, so the results may be comparable.

In summary, AstraZeneca conducted two series of studies targeting the Cbl-b site: HTS screening and information-driven approaches, publishing two articles. However, the articles did not mention any subsequent optimization of clinical candidate molecules based on these two types of molecules. For those interested in the previous discoveries from Nurix molecules and AstraZeneca's HTS series, more information is available.

Look at an example of a biotech company developing FIC.

AstraZeneca Reports New Chemical Series of Cbl-b Inhibitors

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors, J Med Chem, 2024 Jan 16