Overview

This case study demonstrates how Excelra applied a six-stream, multi-evidence framework to identify and rank neuroinflammatory and neurodegenerative indications for an existing JH2-domain-binding kinase inhibitor. Integrating interactome analysis, human genetics, transcriptomics, drug–disease signature matching, drug–drug signature similarity, and structural cheminformatics, the engagement delivered a tiered shortlist of high-priority indications—led by Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder—backed by clear mechanistic rationale and a scalable evidence-scoring framework.

Our client

A U.S. biopharmaceutical company advancing a JH2-domain-binding kinase inhibitor program. With the asset already validated in its primary indication, the client was evaluating where the inhibitor could deliver additional therapeutic value—specifically across neuroinflammatory and neurodegenerative diseases where kinase-mediated cytokine signalling and immune regulation are implicated.

Client’s challenge

A U.S. biopharmaceutical company had a promising asset — a JH2-domain-binding kinase inhibitor — and a high-stakes strategic question: where else could it work? The kinase at its center sits at the crossroads of cytokine signalling and immune regulation, which makes it an attractive target well beyond the drug’s original therapeutic focus. But “attractive in principle” is not a development plan. The client needed to know, systematically and without bias, which neuroinflammatory and neurodegenerative diseases the inhibitor could realistically benefit — and which deserved investment first.

Rather than rely on literature review or any single line of evidence, we built a multi-layered evidence-generation framework that evaluates disease relevance from several independent biological angles at once — interactome analysis, human genetics, transcriptomics, drug–disease and drug–drug signature matching, and structural similarity — and distills them into a ranked, mechanistically grounded shortlist of indications.

Client’s goals

• Identify and prioritize novel neuroinflammatory and neurodegenerative indications to expand an existing kinase-inhibitor program.
• Deliver a ranked list of high-priority indications, each supported by clear mechanistic rationale.

The questions behind the brief

The kinase had already proven itself as a therapeutic target through its role in cytokine signalling and immune regulation — but how far that relevance extended across neurological disease remained unclear. To maximize the value of the JH2-domain-binding inhibitor, the client needed a comprehensive, unbiased read on two questions:

• Which neuroinflammatory and neurodegenerative diseases show the strongest biological association with kinase signalling?
• Which of those indications should be prioritized for further translational and clinical evaluation?

Our Approach

Excelra designed an integrated discovery plan that layered six complementary streams of evidence — each interrogating disease relevance from a different biological perspective, and each acting as an independent check on the others.

Figure 1. Solution strategy for the data-driven identification and prioritization of neuroinflammatory and neurodegenerative indications for the JH2-domain-binding kinase inhibitor.

1.  Interactome-Based disease proximity

We analysed a comprehensive human protein–protein interaction network to measure how closely the kinase and its downstream signalling partners sit to disease-associated gene modules.

Figure 2. Protein–protein interaction and pathway analysis used to identify potential indications associated with the kinase of interest.

The analysis revealed significant network connectivity between kinase-associated pathways and genes implicated in neuroinflammation, microglial activation, cytokine signalling, and neurodegenerative processes.

2.  Human genetics & GWAS evidence

We systematically reviewed genome-wide association study (GWAS) datasets to assess the genetic links between kinase-related pathways and neurological diseases. Several neuroinflammatory indications showed strong genetic backing — driven by JAK–STAT and cytokine-signalling components — reinforcing the biological plausibility of kinase modulation.

3.  Transcriptomic & gene expression analysis

Disease-specific gene expression datasets let us characterize dysregulated genes and pathways and evaluate the relevance of kinase-mediated signalling. Multiple neurological disorders carried elevated inflammatory-signalling signatures — consistent with potential responsiveness to kinase inhibition.

4.  Drug–Disease signature matching

We compared disease transcriptomic signatures against drug-induced expression profiles to answer a pointed question: could kinase inhibition actually reverse the disease-associated molecular environment? Several neuroinflammatory disorders showed strong inverse correlations between their disease signatures and kinase-inhibition transcriptional profiles.

5.  Drug–Drug signature similarity

Next, we compared the gene expression signatures associated with kinase inhibition against those generated by approved and investigational drugs across neurological diseases.

Figure 3. Drug–gene signature analysis used to identify drugs and compounds with signatures similar to the JH2-domain-binding kinase inhibitor, together with their known indications.

Where kinase inhibition mirrored the transcriptional patterns of effective therapeutic interventions, we gained additional assurance in those disease areas.

6.  Structural Similarity assessment

Finally, we evaluated compounds structurally similar to the client’s JH2-domain-binding kinase inhibitor and reviewed the pharmacological and clinical evidence tied to related chemical scaffolds using cheminformatics approaches. This surfaced therapeutic areas previously explored with related molecules — and added independent support for pathway modulation by kinase inhibition.

Integrating the evidence

No single line of evidence decides an indication. We developed a weighted scoring framework that integrates all six analytical layers into one objective ranking.

Figure 4. Deep-dive analysis of disease pathophysiology, generating a scientific hypothesis for JH2-domain-binding kinase inhibition.

Each candidate indication was scored across:

• Network proximity and interactome evidence
• Human genetics support
• Transcriptomic relevance
• Disease-signature reversal strength
• Drug-signature similarity
• Translational feasibility and clinical rationale

The integrated scoring system enabled objective, side-by-side prioritization of candidate indications.

Our solution

The framework produced a clear, tiered prioritization of candidate indications:

Together, these results give the client a scalable approach for indication expansion, target validation, and portfolio prioritization across therapeutic areas.

Deliverables

• Ranked list of prioritized neuroinflammatory and neurodegenerative indications
• Comprehensive mechanistic evidence package for each indication
• Integrated evidence scoring framework
• Disease-specific biological rationale summaries
• Strategic recommendations for subsequent validation activities

Business impact

A data-driven expansion strategy — a clear indication-expansion path for the existing JH2-domain-binding kinase-inhibitor program.

Mechanistic rationale — concrete biological links between kinase biology and disease pathology.

Reduced selection risk — far less uncertainty in deciding which indications to pursue.

Sharper focus — downstream translational and clinical effort concentrated on the most promising opportunities.