Big drug, little drug: Capitalising on large molecule progress

What does progress in the large molecule space mean for small molecule drug discovery? With the FDA approving the 100th antibody drug last year, Dr. John Unitt, our Vice President of Immunology and Inflammation Drug Discovery reflects on how well we have exploited this exciting progress with follow-on small molecule drug discovery.

The structure of an antibody drug

Big drug: The structure of an antibody drug


As a drug hunter in the immunology and inflammation therapeutic space, I’ve focused my attention on biologics in this disease area that have paved the way for modulating and clinically validating a range of hard-to-drug biological targets.

You can think of the usual suspects here, like the cytokines, TNFα and IL-17, linked to diseases such as rheumatoid arthritis and psoriasis and validated in the clinic by neutralising antibodies.

These cytokines have complex, multimeric receptors and ligands that have made small molecule approaches hard to stomach and leverage investment for.

Consider TNFα; it’s a hefty trimer ligand engaging an even bigger trimer receptor – on face value, that’s a lot of molecular Velcro to unpick with a single small molecule interaction.

Not surprisingly, small molecule drugs for these high-value biologically validated drug targets are highly desirable but have remained elusive – the so-called “high-hanging fruit”, out of reach at the top of the drug discovery tree.

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A small molecule inhibitor

Little drug: A small molecule inhibitor

Yet since biological drugs appeared in the 2000s, the drug discovery landscape has changed enormously to make small molecule approaches to challenging biological drug targets more appetising.

Let’s look at some of the key drivers.


Targets already validated

Biologics have clinically validated a lot of cytokines and processes, de-risking them as drug targets and providing a well-trodden way forward, making them more attractive for small molecule drug discovery.

No drug modality is perfect, though, and biologics have well-understood advantages and limitations that an equivalent small molecule can overcome.

Property Small molecules Biologics
Size Small MW (< 1 KDa) Large MW (1-200 KDa)
Chemical stability Stable Unstable
Structure Simple Complex
Specificity Low High
Preferred route of administration Oral Parenteral
Tissue permeability High Low
Metabolism Hepatic P450 oxidation and conjugation Nucleases, peptidases/proteinases, hydrolases
Distribution Via blood circulation

Easily distributed

Via blood and lymphatic circulation

Limited distribution

Immunogenicity No Yes
Current drugs 90% 10%
Cost to make Low High


Innovation and smarter technology

Technology has come a long way.

We’ve seen the advent of new hit identification approaches like DNA-encoded compound libraries, fragment screening, and an increased ability to determine and exploit complex receptor and ligand-protein structures.

(neutralising antibody drug)
Follow-on small molecule commercial activity Hit identification strategy
TNFα (Adalimumab) UCB, BMS In silico/Fragment
IL-17 (Ixekizumab) C4X/Sanofi, Dice, Ensemble/Novartis In silico


IL-1β (Canakinumab) None
IL-12/23 (Ustekinumab) None


The future trajectory will be fascinating to follow.

Will the breakthroughs seen for TNFα and IL-17 provide a foundation to catalyse the exploitation of other clinically validated cytokines like IL-1β and TSLP?

Let’s hope so – the patients are waiting!


Author of this blog - Dr John Unitt, VP Inflammation and Immunology

Dr. John Unitt, VP Inflammation and Immunology, Sygnature Discovery

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