BTK Inhibitor Design

Background

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system, leading to inflammation, demyelination, and ultimately neurodegeneration. The pathogenesis of MS is complex and involves dysregulation of the immune system, particularly B cells, which play a key role in the development and progression of the disease. One potential therapeutic target for MS is Bruton's tyrosine kinase (BTK), a signaling protein that is essential for the activation of B cells. In recent years, selective BTK inhibitors have emerged as promising candidates for the treatment of autoimmune diseases, including MS.

Method and Disscussions

Biogen published an important article in the journal JMC describing the discovery of the clinical candidate BIIB129 (25), a structurally unique and brain-penetrating BTK-targeted covalent inhibitor with an unprecedented binding mode leading to its high kinome selectivity. From a clinical safety standpoint, the physicochemical properties of "H3" binders such as fenebrutinib30, remibrutinib, and BIIB09136 are not conducive to targeting BTK in the CNS despite the outstanding selectivity they exhibit, whereas BIIB129(25) has been found to be highly selective in the disease-associated preclinical in vivo model of CNS B cell proliferation demonstrated efficacy in targeting B cells and myeloid cells, including CNS-resident microglia located in the meninges, perivascular spaces, and CNS parenchyma of patients with multiple sclerosis, demonstrated a favorable safety profile, is suitable for clinical development as an immunomodulatory therapy for MS, and the total daily human dose is expected to be low.

Figure 1. Selected BTK inhibitors of different binding modes are reported in the literature.

Methods and Discussion

The researchers found that compound 10 showed good selectivity for 7 of the 403 kinases tested. The Covalent docking function in SeeSAR's Docking module was used here to predict the binding behavior of compound 10 in BTK.

Figure 2. X-ray cocrystal structure and binding mode of 25 (cyan; PDB 8TU4) in the active site of BTK.

Modification of the seven-membered ring structure was performed to improve the stability of CYP-mediated metabolism while maintaining the desired potency, kinome selectivity, and brain permeability properties. Here it was used ReCore for backbone replacement, imposing pharmacophore restriction to retrieve the non-aromatic ring. The final compound 25 (BIIB129) was obtained, which in addition to excellent selectivity, has brain permeability as well as safety, but its bioavailability is low and there is still room for further improvement.

Figure 3. KINOMEscan, Eurofins DiscoverX, for compounds 25 (a) and 27 (b) at 1 μM concentration. Ten and 5 out of 403 kinases were inhibited with S(10) selectivity scores of 0.025 and 0.012, respectively.

Conclusions

The preclinical characterization of BIIB129 has unveiled its promising profile as a novel therapeutic agent for the treatment of MS. By selectively targeting BTK and demonstrating brain penetration, BIIB129 holds the potential to modulate aberrant immune responses within the central nervous system, thereby offering a more focused approach to managing MS pathology. The findings from this study not only underscore the therapeutic potential of BIIB129 but also highlight the importance of designing drugs that can effectively penetrate the central nervous system for the treatment of neurological disorders. Further clinical investigations are warranted to evaluate the safety and efficacy of BIIB129 in MS patients, with the hope of translating these preclinical discoveries into tangible benefits for individuals living with this challenging autoimmune disease.

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