The Power of Three: A Route to Smarter Drug Discovery

Discipline Integration: Getting to the Root of a Drug Discovery Issue

Challenges in drug discovery are common; however, they are rarely rooted within a single scientific discipline.

For example, a compound may fail to demonstrate efficacy because exposure is too low. Exposure may be limited by poor solubility. Poor solubility may be caused by an unsuitable solid form. Alternatively, the problem may stem from a high clearance, poor permeability, or a lack of target engagement.

Without the collaboration between multiple disciplines, determining the root cause of poor performance can be difficult, resulting in unnecessary delays and inefficient development strategies.   

At Sygnature Discovery, our DMPK, Form & Formulation (F&F) and in-vivo Pharmacology teams are integrated throughout the discovery process, bringing specialist expertise into programs at the stages where they deliver the greatest value. Housed on the same site, this integrated approach enables exposure, efficacy, and development challenges to be assessed collectively rather than in isolation. By identifying potential barriers early and selecting the most appropriate development strategy, teams can make better-informed decisions, reduce program risk and accelerate candidate progression.

Understanding the Molecule

Pharmacology teams are for answering one fundamental question:

Does a compound produce the desired biological effect?

However, meaningful results from efficacy studies are dependent on a compound being sufficiently exposed during in vivo studies.

If drug concentrations never reach therapeutic levels, researchers may be unable to determine whether:

• The target is biologically relevant

• The molecule is ineffective as a therapy

• Exposure is limiting efficacy

This is where DMPK becomes essential.

DMPK Explains why Exposure is Low

in-vivo Pharmacology and DMPK together help define the target exposure required to achieve a therapeutic effect. This target exposure then guides formulation strategy and dose design. Exposure also becomes particularly important when compounds progress into preclinical toxicology studies, where sufficient exposure and dose proportionality are required to establish meaningful safety margins.

DMPK identifies the root cause of exposure limitations:

• High clearance
• Poor permeability
• First-pass metabolism
• Solubility limitations

Understanding these mechanisms prevents teams from pursuing inappropriate solutions. Incorrectly diagnosing the cause of poor performance can lead to unnecessary chemistry campaigns, repeated studies and significant delays in program progression.

For example:

• A formulation cannot fix intrinsically high clearance
• A medicinal chemistry campaign may be unnecessary if the issue is simply poor dissolution

Without DMPK, valuable time may be spent solving the wrong problem.

F&F Provide Solutions

Once exposure limitations are understood, F&F scientists can design targeted strategies to overcome them.

These may include:

Solid Form Selection

Choosing the most suitable:

• Polymorph
• Salt form
• Crystal form

Enabling Formulations

Development of:

• Amorphous solid dispersions (lyophilized or spray dried)
• Lipid formulations
• Liquid formulations

These approaches can improve dissolution, absorption and systemic exposure without altering the molecule itself. Working together, in-vivo Pharmacology, DMPK and Form & Formulation teams use target exposure data to develop the most appropriate strategy for candidate progression.

The Value in Integration

The real value emerges when the Big Three: DMPK, in vivo Pharmacology and Form & Formulation work together. Rather than waiting for studies to be completed sequentially, integrated teams can review emerging PK, efficacy and formulation data in real time, refining strategies before small issues become major development challenges.

However, successful drug discovery rarely depends on three disciplines alone. As programs evolve, expertise from Medicinal Chemistry, Bioscience, Protein & Structural Sciences, CADD and In Vivo Models can be integrated as required. This provides additional insight into target biology, molecular design, developability and translational strategy. Together, these disciplines form a continuous feedback network that helps teams identify the right problem, apply the right solution and maintain project momentum.

At the center of this approach sit the Big Three, driving decisions around exposure, efficacy and formulation. Surrounding disciplines provide complementary expertise, ensuring challenges can be addressed from multiple perspectives while maintaining a clear focus on candidate progression.

This approach can:

• Reduce development risk
• Shorten project timelines
• Avoid unnecessary redesign cycles
• Improve candidate selection
• Reduce program attrition

Historically, Form & Formulation expertise has been introduced only after significant development challenges have emerged. However, lessons from industry examples highlight the importance of understanding solid form, exposure and developability risks much earlier in the discovery process.

For instance, after the launch of Ritonavir a new polymorphic form emerged in the product that was significantly more stable, but substantially less soluble than the marketed form. The appearance of this previously unidentified polymorph reduced drug dissolution and forced the product to be withdrawn and reformulated.

Although extreme, the example highlights how inadequate understanding of solid form can introduce serious development risks. At Sygnature Discovery, Form & Formulation scientists work alongside DMPK and Pharmacology teams from the outset, enabling the early identification of:

• Polymorphism risks
• Solubility limitations
• Exposure challenges
• Stability and manufacturability challenges

This approach can prevent promising compounds from being deprioritized due to limitations that may be resolved through form or formulation strategies. By assessing these factors collectively rather than in isolation, potential barriers can be identified and addressed before they impact program timelines. This allows teams to make critical progression decisions with greater confidence and supports the selection of candidates with the highest likelihood of development success.

Looking at Integrated Problem Solving at Sygnature Discovery

Integrated teams are uniquely positioned to determine whether exposure limitations arise from poor solubility, high clearance, poor permeability or insufficient target engagement, ensuring resources are focused on the correct solution.

While DMPK, in vivo Pharmacology and Form & Formulation form the core decision-making engine, they do not operate in isolation. As programs progress, expertise from Medicinal Chemistry, Bioscience, Protein & Structural Sciences, CADD and In Vivo Models can be brought into the project wherever they deliver the greatest value. This wider network provides additional insight into target biology, molecular design, protein production, developability and translational relevance. Rather than approaching challenges through a series of disconnected handoffs, Sygnature Discovery’s integrated structure enables information to flow continuously between disciplines, creating a feedback loop that supports smarter and more efficient project progression.

By identifying risks earlier, integrated teams help avoid unnecessary studies, reduce compound consumption, minimize redesign cycles, and improve overall project efficiency. For our clients, this means more confident decision-making, lower development risk and faster progression of promising drug candidates.