AstraZeneca Reports Novel Information-Driven Cbl-b Inhibitor Series with Optimized Metabolic Profile

Feb 23, 2024 06:30 CST Updated 06:30

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. Apart from AstraZeneca, several other star companies are also following (see figure below). In China, BeiGene and Simcere Zaiming have also made arrangements in this target.

So here we can demystify a bit: large foreign companies or star biotechs don’t necessarily avoid fast-follow (in fact, many do), they just also have the ability to develop FICs. Regarding AstraZeneca's two Cbl-b series, from a discovery perspective, the HTS-screened series is of course more novel and interesting. However, from a practical standpoint, it’s uncertain which series will ultimately succeed. In fact, neither of AstraZeneca’s two articles mentioned moving forward to a clinical candidate, so it’s possible neither will be pursued further.Moreover, different people have different understandings of "first-in-class," such as 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 belongs toFast-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 the improvement of metabolism. For the Nurix molecule, they identified the piperidine moiety of molecule 1 as the primary metabolic site through Met ID. Therefore, the goal was to create structurally different 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). The activities of molecules 8 and 9 are acceptable, 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 decrease in activity of molecule 10 might 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 lower by a whole unit—why is that? If interested, perhaps it’s worth considering and testing with 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 HB 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 compound 31, cellular activity reaches the best-reported level in the series. Additionally, the article mentions that compared with 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 make 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 in 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 more information on the previous discovery of Nurix molecules and the AstraZeneca HTS series, you may refer to the following:

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

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