Drugging Challenging Cancer Targets Using Fragment-Based Methods

There are many highly validated cancer targets that are difficult or impossible to drug due to the absence of suitable pockets that can bind small molecules. Fragment-based methods have been shown to be a useful approach for identifying ligands to proteins that were previously thought to be undruggable. In this review, I will give an overview of fragment-based ligand discovery and provide examples from our own work on how fragment-based methods were used to discover high affinity ligands for challenging cancer drug targets.

• Publication year

  2025

• Venue

  Chemical Reviews

• Publication date

  2025-03-05

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.chemrev.4c00892PMID 40043012PMCID 11951080
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed/Refractory Hematologic Malignancies

  2024cited by this paper
• Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl-1 BH3 Mimetics

  2024cited by this paper
• Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors

  2024cited by this paper
• Targeting KRAS in cancer

  2024cited by this paper
• Targeting cancer with small molecule pan-KRAS degraders

  2024cited by this paper
• BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

  2024cited by this paper
• Fragment-based drug discovery supports drugging 'undruggable' protein-protein interactions.

  2023cited by this paper
• Pan-KRAS inhibitor disables oncogenic signalling and tumour growth

  2023cited by this paper
• Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

  2023cited by this paper
• Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.

  2022cited by this paper
• Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models

  2022cited by this paper
• Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRASG12C Inhibitor

  2022cited by this paper
• Targeting MCL-1 in cancer: current status and perspectives

  2021cited by this paper
• Acute myeloid leukemia: current progress and future directions

  2021cited by this paper
• Fragment-based covalent ligand discovery

  2021cited by this paper
• Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3).

  2021cited by this paper
• Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC inhibitors using fragment-based methods and structure-based design.

  2020cited by this paper
• WDR5 is a conserved regulator of protein synthesis gene expression

  2020cited by this paper
• MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

  2020cited by this paper
• Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance

  2019cited by this paper
• Clinical candidates modulating protein-protein interactions: The fragment-based experience.

  2019cited by this paper
• Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity

  2019cited by this paper
• Fragment-based screening of programmed death ligand 1 (PD-L1).

  2019cited by this paper
• Discovery and Structure-Based Optimization of Potent and Selective WD repeat domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.

  2019cited by this paper
• Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Protein-Protein Interaction.

  2019cited by this paper
• Targeting WDR5: A WINning Anti-Cancer Strategy?

  2019cited by this paper
• Drugging an undruggable pocket on KRAS

  2019cited by this paper
• Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

  2019cited by this paper
• Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design.

  2018cited by this paper
• Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.

  2018cited by this paper
• Discovery of Potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design.

  2018cited by this paper
• Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.

  2018cited by this paper
• Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.

  2018cited by this paper
• Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.

  2018cited by this paper
• Discovery and biological characterization of potent myeloid cell leukemia‐1 inhibitors

  2017cited by this paper
• Fragment-based drug discovery and its application to challenging drug targets.

  2017cited by this paper
• Twenty years on: the impact of fragments on drug discovery

  2016cited by this paper
• Discovery of Inhibitors of Protein–Protein Interactions Using Fragment‐Based Methods

  2016cited by this paper
• Venetoclax: First Global Approval

  2016cited by this paper
• Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.

  2016cited by this paper
• Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia.

  2016cited by this paper
• Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC.

  2015cited by this paper
• Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.

  2015cited by this paper
• A method for the second-site screening of K-Ras in the presence of a covalently attached first-site ligand

  2014cited by this paper
• Fragment-Based Screening of the Bromodomain of ATAD2

  2014cited by this paper
• The role of ligand efficiency metrics in drug discovery

  2014cited by this paper
• Fragment-based drug discovery using NMR spectroscopy

  2013cited by this paper
• Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach.

  2013cited by this paper
• ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

  2013cited by this paper
• Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor

  2013cited by this paper
• Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.

  2013cited by this paper
• K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

  2013cited by this paper
• Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17

  2012cited by this paper
• Vemurafenib: the first drug approved for BRAF-mutant cancer

  2012cited by this paper
• Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation.

  2012cited by this paper
• Molecular complexity and fragment-based drug discovery: ten years on.

  2011cited by this paper
• Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.

  2010cited by this paper
• Fragment-based drug discovery

  2009cited by this paper
• ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.

  2008cited by this paper
• Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.

  2007cited by this paper
• Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo.

  2006cited by this paper
• A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.

  2006cited by this paper
• Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis.

  2006cited by this paper
• Non-peptidic small molecule inhibitors of XIAP.

  2005cited by this paper
• An inhibitor of Bcl-2 family proteins induces regression of solid tumours

  2005cited by this paper
• Fragment-based drug discovery.

  2004cited by this paper
• Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.

  2003cited by this paper
• Identification of novel inhibitors of urokinase via NMR-based screening.

  2000cited by this paper
• Design of adenosine kinase inhibitors from the NMR-based screening of fragments.

  2000cited by this paper
• Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis.

  1999cited by this paper
• NMR-based discovery of phosphotyrosine mimetics that bind to the Lck SH2 domain.

  1999cited by this paper
• Structure of Bcl-xL-Bak Peptide Complex: Recognition Between Regulators of Apoptosis

  1997cited by this paper
• NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.

  1997cited by this paper
• Discovering High-Affinity Ligands for Proteins

  1997cited by this paper
• Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR

  1997cited by this paper
• Stromelysin Inhibitors Designed from Weakly Bound Fragments: Effects of Linking and Cooperativity

  1997cited by this paper
• Discovering High-Affinity Ligands for Proteins: SAR by NMR

  1996cited by this paper
• X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death

  1996cited by this paper
• On the attribution and additivity of binding energies.

  1981cited by this paper

• Beyond Binding Affinity: Detailed Profiling of Protein-Ligand Interactions with Time-Resolved FRET.

  2026cites this paper
• NMR in the age of modern biomedical research and drug discovery.

  2025cites this paper
• Pharmacophore-driven antibody discovery on the yeast surface

  2025cites this paper