AbbVie Submits Prospectus for ABBV-712, a Selective TYK2 Inhibitor, with Structural Comparison to Deucravacitinib and TAK-279
AbbVie
Innovative Drug Developer
Bristol-Myers Squibb
Biopharmaceutical and Nutritional Product R&D and Sales
Takeda
Biopharmaceutical Manufacturer
Recently, researchers from AbbVie published an article in JMC, describing the discovery process of their TYK2 clinical candidate ABBV-712.
The following are TYK2 clinical molecules from several other companies. The molecule in the red box has been approved, namely BMS's deucravacitinib, and the molecule in the blue box is TAK-279, which Takeda acquired from Nimbus. It is currently in Phase III clinical trials with positive results.
Deucravacitinib was approved by the FDA in September last year and has recently been approved in China, with a time interval of approximately 1 year and 1 month.
Back to AbbVie's molecular discovery. Compound 6 was the result of their initial optimization following the HTS hit. Although Compound 6 was already a promising starting point for further optimization, it suffered from poor thermodynamic solubility. Likely due to this issue, the co-crystal structure they resolved was of Compound 7, despite its lower activity.
With the binding mode of molecule 7 in hand, as well as insights into TYK2 and JAK1/2Structural Comparison from the Perspective of Pocket Shape, Size, and Electrostatic PotentialThey believe that the pseudo-gatekeeper Thr687 in the TYK2 JH2 domain is a key residue, which, on the one hand, makes the back pocket more accessible, and on the other hand, causes a different swing range of Lys642, offering an opportunity for selectivity compared with other JAK kinases.
Specifically, the cyclopropyl group of molecule 7 occupies the back pocket, and the double hydrogen bonds formed between the molecule and Lys642 are key factors in enhancing selectivity (although they also impact activity). At the same time, it can be observed that the cyclopropyl group has some clashes with the protein, which explains this as well.WhyMolecule 7 is less active than molecule 6 (with a methyl group at the corresponding position).
Discussion on Deucravacitinib and Deuteration
A Brief Discussion on Two TYK2 Inhibitors with Better Selectivity
Further MolecularDesignUsing some modeling and computational analysis, below are two examples, one is dihedral analysis, and the other isDuring the MD processInteraction maintenance status, not detailed.
SAR is also not described in detail. One interesting point is thatMethoxytetrahydrofuran Replacement for Sulfonamide, which is also an in silico idea,Improved solubilityAndMaintained activity.
In summary, by optimizing activity, selectivity, PK, CYP, etc., the final candidate molecule 21 (i.e., ABBV-712) was obtained.
Its PK and some efficacy results are shown in the figure below.
Fast forward to the second part, which is a structural comparison with BMS molecules and Takeda/Nimbus molecules.
The following figures are all from the same perspective. First, AbbVie's molecules are reported to have crystal structures for two of them, molecule 7 and molecule 14.
The following two are the previously reported molecules from BMS and Takeda/Nimbus.
Finally, the protein is hidden, and the superposition of small molecule binding poses is performed.
Although the chemical structures are different, there are some commonalities in the binding patterns, especially at key binding features. The hinge region is not mentioned here, but the diagram below highlights three other areas.
One is the carbonyl group (orange arrow) that forms one of the double hydrogen bonds with Lys642, which perfectly aligns in the binding pose; another is the methyl group (gray-white) occupying the back pocket (also known as the alanine pocket in TYK2); the last one is the methoxy O in the Nimbus molecule and the tetrahydrofuran O in the AbbVie molecule.In the binding poseAlso in the same location.
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