Design of a highly selective, allosteric, picomolar TYK2 inhibitor using novel FEP+ strategies

Design challenge

JAK/TYK kinases are key signaling molecules in a variety of inflammatory diseases. In psoriasis, for example, inflammation is driven by increased interferon and cytokine release, which is regulated by these JAK/TYK kinases. To date, marketed drugs have targeted the JH1 kinase domain of these multi-domain protein complexes. However, these approved JAK inhibitor drugs have known safety issues related to heart function, clotting, and thrombosis due to non-selective inhibition of other JAK kinases (JAK1, JAK2, JAK3).

Scientists from Nimbus Therapeutics began working on this challenge with the goal of developing a potent and highly selective TYK2 inhibitor that improved clinical activity while avoiding off-target side effects. In 2016, Nimbus and Schrödinger scientists teamed up on the project, first starting by targeting the catalytic JH1 kinase domain and later pivoting to the regulatory domain JH2 based on the release of promising data in the literature.

Pivot to TYK2 JH2 allosteric domain enabled by FEP+ de novo core design and virtual screening

Around the same time, new research from scientists at Bristol Myers Squibb confirmed that highly selective TYK2 inhibitors could be achieved by targeting the JH2 allosteric site.⁴ The project team made the important decision to pivot — changing their focus to developing a TYK2 inhibitor targeting the JH2 regulatory domain. This biological validation along with the deep structural enablement available for TYK2 and the JAK family member pseudokinase domains provided the team with an opportunity to engage in a multi-pronged, structure-based design strategy. 

FEP+ was used to guide compound design strategies with de novo core exploration resulting in the identification of the pyrrazolono-pyridine and pyridino-imidazole cores, which displayed promising potency and domain selectivity but were hindered by several ADME liabilities (Figure 2).⁵ A large-scale structure-based virtual screen enabled screening of 2.4M commercially available compounds against an ensemble of receptor models based on known JH2 crystal structures from the PDB using Glide followed by WScore — resulting in three structurally distinct hit classes (Figure 2).⁵ Each hit displayed some promising level of JH2 affinity, but the pyrazolo-pyrimidine core was chosen for further exploration based on its steric and electronic similarity to the imidazopyridazine core published by BMS. These structure-based design efforts allowed the team to identify multiple picomolar JH2 scaffolds from these hits in a period of 3 months. 

In order to progress these hits, the team again employed an MPO paradigm with large scale modeling, this time in two stages. First, quick modeling of physicochemical properties, as well as passive permeability, was performed to ensure the compounds progressed to resource intensive FEP+ models and synthesis would stay in a reasonable chemical space. Second, compounds were put through rigorous FEP+ potency predictions — targeting picomolar potency. All models and MPOs were collected in LiveDesign, Schrödinger’s cloud-based enterprise informatics platform, within different LiveReports for different design objectives which the team would review together. Using this MPO strategy, the team carried out parallel ligand FEP+ modeling against TYK2 JH2 as well as other JAK family kinase domains in order to design analogs with high JH2 affinity and JAK family domain selectivity. 

Within two years of pivoting to the allosteric TYK2 program, the team had declared a development candidate. NDI-034858 is a picomolar inhibitor tuned precisely to target the JH2 domain of TYK2, as shown by its exquisitely clean selectivity profile (Figure 3). 

In November 2022, Nimbus reported positive topline results for once-daily, oral dosing with NDI-034858 in Phase 2b clinical trials.⁶ Furthermore, by February 2023 Takeda had acquired the program.⁷ Now referred to as TAK-279, this highly selective, oral TKY2 inhibitor has best-in-class potential among allosteric inhibitors for treatment of psoriasis, as well as multiple other immune-mediated diseases.⁸