Marc Flajolet; Yashoda SUNKARI

WO2024097744A2

Link: https://patents.google.com/patent/WO2024097744A2/en?

Abstract

The present invention provides methods of generating diverse chemical structures on DNA through Wittig olefination of novel on-DNA phosphorane ylides and Homer- Wadsworth-Emmons reaction of on-DNA β-keto phosphonates. The methods of this invention provide access to DNA-encode libraries (DELs) of diverse peptides, peptidomimetics, chalcone-based molecules, and the like.

Gavin W. Collie*, Bryony Ackroyd, Catriona Corbishley, Daniel H. O’Donovan, Alex Edwards, Andrea Gohlke, Xiaoxiao Guo, Bethan Howells, Yuliang Li, Andrew Madin, Alexander G. Milbradt, Emma L. Rivers*,Sandeep K. Talapatra, Elizabeth Underwood, and Alice Webb

ACS Med. Chem. Lett. 

DOI: 10.1021/acsmedchemlett.5c00396

Abstract

NSD2 is a key epigenetic regulator and has received considerable attention as a drug target due to its well-documented role in tumorigenesis. We report here a DNA-encoded library screen targeting the PWWP1 domain of NSD2 from which we discovered novel, potent, and selective binders. Furthermore, these compounds were used to develop a novel crystal system, increasing our understanding of the folding of this domain. Together, these results provide a solid molecular and structural basis for the further study of the PWWP1 domain of NSD2 as a cancer drug target.

In the pursuit of new therapeutics, the initial phase of identifying chemical starting points—or "hits"—is crucial. Among the most prominent strategies employed in modern drug discovery are DNA-Encoded Libraries (DEL), *High-Throughput Screening (HTS), and Fragment-Based Drug Discovery (FBDD). Each offers a distinct philosophy and set of advantages for navigating the vastness of chemical space.

The following table provides a high-level overview of their core characteristics, placing emphasis on the innovative DEL approach.

Summary and Strategic Outlook

The choice between DEL, HTS, and FBDD is rarely a question of which technology is superior, but rather which is the most appropriate for a specific project's goals and constraints.

* DEL has emerged as a powerful tool for its ability to screen enormous chemical space in a single experiment, offering a highly cost-effective method for generating novel starting points, especially for emerging or undrugged targets.

* HTS remains the established and reliable workhorse for many organizations, providing a direct route to potent hits from existing libraries.

* FBDD is often lauded for its efficiency and the high quality of its lead compounds, which typically exhibit excellent optimization potential.

A forward-looking R&D strategy often involves integrating these approaches. For instance, a novel hit discovered through a DEL screen can be optimized using the principles of FBDD, while HTS libraries can be augmented with novel chemotypes identified from DELs. This complementary use of technologies leverages the unique strengths of each, creating a more robust and effective drug discovery pipeline.

Developing new medicines demands smart technology and powerful tools. DNA-encoded library (DEL) technology, with its unique ability to rapidly screen billions of compounds to identify small molecule hits, has transformed drug discovery. HitGen Inc. is raising the bar with the introduction of OpenDEL™ 5.0 – featuring a total of 4 billion diverse compounds designed to tackle challenging biological targets. OpenDEL™ 5.0 comes in a convenient kit format that is accessible to scientists in industry and academia alike.

Key Improvements:

✔ Expanded Chemical Diversity: 4 billion Compounds
• Increased Library Size: Now with 25% more compounds, OpenDEL™ 5.0 offers 3.8 billion small molecules compounds and 200 million peptide compounds to further expand chemical space for targeting protein-protein-interactions (PPI).

• Encompassing Library Design: 59 distinct libraries provide a broad range of chemistries to address different types of targets and discovery challenges.

✔ Optional Macrocycle Library: Unlocking Challenging Targets
• A dedicated macrocycle library: Available as an add-on, featuring 4-10 amino acids in the ring. Comes with a linear peptide control library.

• Dual-Kit Flexibility: Choose between OpenDEL™-Small Molecules or OpenDEL™-Macrocycle – or combine both for maximum coverage.

✔ Streamlined Workflow & Faster Access

• Redesigned protocols: Intuitive visual guides simplify key steps, reducing onboarding time.

• Expedited delivery: Next-day shipping available to minimize wait time

OpenDEL™ Physicochemical Properties Distribution

OpenDEL™ compounds are designed with balanced physicochemical properties, ensuring high-quality hits from screening to development.

OpenDEL™ in the Literature

1. Grogan A, Ahn S, Israel D, et al. Abstract P2154: A novel allosteric modulator of the β1AR identified by DNA-encoded small molecule library screening demonstrates unique pharmacology and function. Circ Res. 2023;133(Suppl 1):AP2154. doi:10.1161/res.133.suppl_1.P2154

2. Zhang, C.; Pitman, M.; Dixit, A.; Leelananda, S.; Palacci, H.; Lawler, M.; Belyanskaya, S.; Grady, L.; Franklin, J.; Tilmans, N.; Mobley, D. L. Building Block-Based Binding Predictions for DNA-Encoded Libraries. J. Chem. Inf. Model. 2023, 63 (16), 5120– 5132,  DOI: 10.1021/acs.jcim.3c00588

3. Brooun A, Fagan P, Bergqvist S, et al. Identification and characterization of inhibitors of SHOC2-MRAS-PP1C complex assembly [published online ahead of print April 2025]. Cancer Res. 2025;85(8_Supplement_1):3152. doi:10.1158/1538-7445.AM2025-3152

4. Wellnitz, J. et al. Enabling open machine learning of DNA encoded library selections to accelerate the discovery of small molecule protein binders. Preprint at https://doi.org/10.26434/chemrxiv-2024-xd385 (2024).

OpenDEL™ Use and Customer Testimonials

Begin Your Exploration Today

OpenDEL™ 5.0 is now available worldwide. Let HitGen help you with your next drug discovery breakthrough.  

Tony Georgiev, Francesca Migliorini, Andrea Ciamarone, Marco Mueller, Ilaria Biancofiore, Pinuccia Faviana, Francesco Bartoli, Young Seo Park Kim, Lucrezia Principi, Ettore Gilardoni, Gabriele Bassi, Nicholas Favalli, Emanuele Puca, Dario Neri, Sebastian Oehler & Samuele Cazzamalli 
Nature Biomedical Engineering (2025)

DOI: 10.1038/s41551-025-01432-6

Abstract

Improving the specificity of prostate cancer treatment requires ligands that bind selectively and with ultra-high affinity to tumour-associated targets absent from healthy tissues. Prostatic acid phosphatase has emerged as an alternative target to prostate-specific membrane antigen, as it is expressed in a broader subset of prostate cancers and is not detected in healthy organs such as the salivary glands and kidneys. Here, to discover selective binders to prostatic acid phosphatase, we constructed two DNA-encoded chemical libraries comprising over 6.7 million small molecules based on proline and phenylalanine scaffolds. Screening against the purified human prostatic acid phosphatase yielded OncoACP3, a small organic ligand with picomolar binding affinity. When radiolabelled with lutetium-177, OncoACP3 selectively accumulated in enzyme-expressing tumours with a long residence time (biological half-life greater than 72 h) and a high tumour-to-blood ratio (>148 at 2 h after administration). Lutetium-177-labelled OncoACP3 cured tumours in mice at low, well-tolerated doses. Its conjugation to the cytotoxic agent monomethyl auristatin E facilitated tumour-selective payload deposition, resulting in potent anti-tumour activity. The modular structure of OncoACP3 supports flexible payload delivery for the targeted treatment of metastatic prostate cancer.

Summary

Philochem’s research team successfully identified high-affinity ligands targeting prostate-specific membrane antigen (ACP3) using DNA-encoded library (DEL) technology. The study demonstrates a rapid and efficient path from hit identification to preclinical validation, highlighting DEL’s utility in accelerating radioligand therapy development.

Highlights

1. High-Affinity Ligand Discovery

- Two phosphonate-focused DELs were screened against ACP3, yielding enriched hits with strong binding motifs.

- Optimized compounds achieved sub-nanomolar inhibition (SPR-confirmed) and >100-fold improved affinity versus the original ligand.

- Fluorophore-conjugated ligands selectively stained ACP3-expressing prostate cancer cells, confirming target engagement.

2. Therapeutic Efficacy in Preclinical Models

- 177Lu-labeled conjugates showed ~70 %ID/g tumor uptake in xenografts with minimal off-target accumulation and slow washout.

- Significant tumor regression was observed, outperforming a reference radioligand derived from earlier inhibitors.

- Small-molecule drug conjugates (cleavable linker + MMAE payload) also demonstrated potent antitumor activity.

Conclusion

Philochem’s work delivers a robust pipeline of ACP3-targeting ligands with translational potential in radioligand therapy and antibody-free drug conjugates. It validates DEL as a key enabling technology for accelerating cancer therapeutic discovery.

DEL (DNA-encoded library) technology is transforming how we screen billions of compounds for new drugs—but is it truly a game-changer? What are its biggest breakthroughs, and where does it fall short? Could this be the future of pharmaceuticals, or are there still hurdles to overcome? Share your insights on the promises and challenges of DEL tech!