{"id":17078,"date":"2022-01-18T09:36:20","date_gmt":"2022-01-18T09:36:20","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/big-drug-little-drug-capitalising-on-large-molecule-progress\/"},"modified":"2022-01-18T09:36:20","modified_gmt":"2022-01-18T09:36:20","slug":"big-drug-little-drug-capitalising-on-large-molecule-progress","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/big-drug-little-drug-capitalising-on-large-molecule-progress\/","title":{"rendered":"Big drug, little drug: Capitalising on large molecule progress"},"content":{"rendered":"

What does progress in the large molecule space mean for small molecule drug discovery? <\/strong>With the FDA approving the 100th antibody drug<\/a> last year, Dr. John Unitt<\/a>, 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.<\/strong><\/span><\/p>\n

\"The

Big drug: The structure of an antibody drug<\/p><\/div>\n

\u00a0<\/p>\n

As a drug hunter in the immunology and inflammation therapeutic space, I\u2019ve 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.<\/span><\/p>\n

You can think of the usual suspects here, like the cytokines, TNF\u03b1 and IL-17, linked to diseases such as rheumatoid arthritis and psoriasis and validated in the clinic by neutralising antibodies.<\/span><\/p>\n

These cytokines have complex, multimeric receptors and ligands that have made small molecule approaches hard to stomach and leverage investment for.<\/span><\/p>\n

Consider TNF\u03b1; it\u2019s a hefty trimer ligand engaging an even bigger trimer receptor \u2013 on face value, that\u2019s a lot of molecular Velcro to unpick with a single small molecule interaction.<\/span><\/p>\n

Not surprisingly, small molecule drugs for these high-value biologically validated drug targets<\/a> are highly desirable but have remained elusive \u2013 the so-called \u00ab\u00a0high-hanging fruit\u00a0\u00bb, out of reach at the top of the drug discovery tree.<\/span><\/p>\n

Download John\u2019s eBook on anti-inflammatory drug discovery<\/strong><\/a><\/h4>\n
\"A

Little drug: A small molecule inhibitor<\/p><\/div>\n

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.<\/span><\/p>\n

Let\u2019s look at some of the key drivers.<\/span><\/p>\n

\u00a0<\/p>\n

Targets already validated<\/strong><\/h2>\n

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.<\/span><\/p>\n

No drug modality is perfect, though, and biologics have well-understood advantages and limitations that an equivalent small molecule can overcome.<\/span><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Property<\/strong><\/td>\nSmall molecules<\/strong><\/td>\nBiologics<\/strong><\/td>\n<\/tr>\n
Size<\/td>\nSmall MW (< 1 KDa)<\/td>\nLarge MW (1-200 KDa)<\/td>\n<\/tr>\n
Chemical stability<\/td>\nStable<\/td>\nUnstable<\/td>\n<\/tr>\n
Structure<\/td>\nSimple<\/td>\nComplex<\/td>\n<\/tr>\n
Specificity<\/td>\nLow<\/td>\nHigh<\/td>\n<\/tr>\n
Preferred route of administration<\/td>\nOral<\/td>\nParenteral<\/td>\n<\/tr>\n
Tissue permeability<\/td>\nHigh<\/td>\nLow<\/td>\n<\/tr>\n
Metabolism<\/td>\nHepatic P450 oxidation and conjugation<\/td>\nNucleases, peptidases\/proteinases, hydrolases<\/td>\n<\/tr>\n
Distribution<\/td>\nVia blood circulation\n

Easily distributed<\/p><\/td>\n

Via blood and lymphatic circulation\n

Limited distribution<\/p><\/td>\n<\/tr>\n

Immunogenicity<\/td>\nNo<\/td>\nYes<\/td>\n<\/tr>\n
Current drugs<\/td>\n90%<\/td>\n10%<\/td>\n<\/tr>\n
Cost to make<\/td>\nLow<\/td>\nHigh<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

\u00a0<\/p>\n

Innovation and smarter technology<\/strong><\/span><\/h2>\n

Technology has come a long way.<\/span><\/p>\n

We\u2019ve 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.<\/span><\/p>\n\n\n\n\n\n\n\n
Cytokine <\/strong>
\n(neutralising antibody drug)<\/strong><\/td>\n		Follow-on small molecule commercial activity<\/strong><\/td>\nHit identification strategy<\/strong><\/td>\n<\/tr>\n
TNF\u03b1 (Adalimumab)<\/td>\nUCB, BMS<\/td>\nIn silico\/Fragment<\/td>\n<\/tr>\n
IL-17 (Ixekizumab)<\/td>\nC4X\/Sanofi, Dice, Ensemble\/Novartis<\/td>\nIn silico\n

DEL\/Macrocycle<\/p><\/td>\n<\/tr>\n

IL-1\u03b2 (Canakinumab)<\/td>\nNone<\/td>\n<\/td>\n<\/tr>\n
IL-12\/23 (Ustekinumab)<\/td>\nNone<\/td>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

\u00a0<\/p>\n

The future trajectory will be fascinating to follow.<\/span><\/p>\n

Will the breakthroughs seen for TNF\u03b1 and IL-17 provide a foundation to catalyse the exploitation of other clinically validated cytokines like IL-1\u03b2 and TSLP?<\/span><\/p>\n

Let\u2019s hope so \u2013 the patients are waiting!<\/span><\/p>\n

\u00a0<\/p>\n

\"Author<\/p>\n

Dr. John Unitt, VP Inflammation and Immunology, Sygnature Discovery<\/p>\n

Want to learn more about anti-inflammatory drug discovery? Download our eBook all about i<\/strong>t<\/strong><\/a><\/h4>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":17079,"template":"","category":[29],"class_list":["post-17078","blog","type-blog","status-publish","has-post-thumbnail","hentry","category-non-categorise"],"acf":[],"yoast_head":"\nBig drug, little drug: Capitalising on large molecule progress - Sygnature<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/big-drug-little-drug-capitalising-on-large-molecule-progress\/\" \/>\n<meta property=\"og:locale\" content=\"fr_CA\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Big drug, little drug: Capitalising on large molecule progress - Sygnature\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/big-drug-little-drug-capitalising-on-large-molecule-progress\/\" \/>\n<meta property=\"og:site_name\" content=\"Sygnature\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2026\/02\/sygnature-hit-to-lead-team-collaboration-scaled.webp\" \/>\n\t<meta property=\"og:image:width\" content=\"2560\" \/>\n\t<meta property=\"og:image:height\" content=\"1707\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/webp\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Estimation du temps de lecture\" \/>\n\t<meta name=\"twitter:data1\" content=\"3 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.sygnaturediscovery.com\\\/fr\\\/blog\\\/big-drug-little-drug-capitalising-on-large-molecule-progress\\\/\",\"url\":\"https:\\\/\\\/www.sygnaturediscovery.com\\\/fr\\\/blog\\\/big-drug-little-drug-capitalising-on-large-molecule-progress\\\/\",\"name\":\"Big drug, little drug: Capitalising on large molecule progress - 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