Chk1 pre-clinical application
Structure-guided fragment design delivered V158411, a potent Chk1/Chk2 inhibitor that enhances irinotecan’s anti-tumour activity without added systemic toxicity.
The Challenge
Chk1 is a critical component of the DNA damage response checkpoint, especially in cancer cells. Targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumour activity of DNA-damaging chemotherapy drugs — but only if the combination gains efficacy without also gaining toxicity to normal tissue
Related Publications
Identification of Novel, In Vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design
Massey, A. J. et al., Oncotarget 2015, 6, 35797–35812
Read on Impact JournalsInhibition of Chk1 With the Small Molecule Inhibitor V158411 Induces DNA Damage and Cell Death in an Unperturbed S-Phase
Wayne, J. et al., Oncotarget 2016, 7, 85033–85048
Read on Impact JournalsThe Science
Structure-guided fragment elaboration was used to identify and develop a novel series of Chk1 inhibitors, culminating in the identification of V158411, a potent ATP-competitive inhibitor of Chk1 and Chk2.
V158411 potentiated the anti-tumour activity of irinotecan in a variety of human colon tumour xenograft models, without additional systemic toxicity.
These results demonstrate the opportunity for combining V158411 with standard-of-care chemotherapeutic agents, to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. V158411 would therefore warrant further clinical evaluation.
X-ray crystal structures of compounds bound to the ATP binding site of Chk1 (PDB: 5DLS).
Key Takeaways
- Novel Chk1 inhibitor series developed by structure-guided fragment elaboration
- V158411 potentiated irinotecan across a variety of human colon xenograft models
- Efficacy gained without additional systemic toxicity — a genuine therapeutic window
- Concluded to warrant further clinical evaluation as a combination partner
Service Areas
Work with us
Vernalis has collaborated with a wide range of partners to enable some of the most challenging therapeutic targets. Present and past collaborators include Servier, Pierre Fabre, Genentech and Lundbeck. Vernalis can support programs with DEL and fragment-based technologies through to establishing full drug discovery programmes for our partners.
Our track record is built on innovation and success in enabling drug discovery and identifying clinical candidates for a wide variety of therapeutic targets.
Research Director and Joint Site Lead
James Murray PhD
Similar Case Studies
Explore how our team overcomes challenges through case studies showcasing our success stories.
-
Hsp90 oral backup pre-clinical candidate
Fragment-based and in silico hits were combined into a novel series of Hsp90 inhibitors, delivering tumour growth regression on oral dosing in a BT474 xenograft model.
Outcome Oral pre-clinical candidate — the follow-on to the intravenous phase II compound. -
DYRK1A and DYRK1B selective inhibitors
A Vernalis and Servier NMR fragment screen delivered two series of potent, selective DYRK1A inhibitors, including the brain-penetrant tool compound 34.
Outcome Two optimised inhibitor series and a selective, brain-penetrant tool compound. -
Non-hydroxamate LpxC inhibitors
A Vernalis and Taisho collaboration used fragment and structure-based methods to deliver a non-hydroxamate LpxC inhibitor with antibacterial activity against P. aeruginosa.
Outcome Antibacterial lead that designs out the hydroxamate zinc-binding group and its selectivity risk. -
LRRK2 crystallographic surrogate
Vernalis engineered crystallographic surrogates of LRRK2 from Chk1 mutants, then used them to design a potent, brain-penetrant inhibitor with confirmed target engagement.
Outcome Target enablement — a crystallisable system, and a brain-penetrant inhibitor designed against it. -
PDHK — application of off-rate screening
SPR off-rate screening of unpurified reaction products drove rapid hit-to-lead progression to selective, sub-100 nM pan-isoform PDHK inhibitors.
Outcome Proprietary off-rate screening validated on a live programme, delivering sub-100 nM leads. -
Hsp90 phase II candidate
Fragment, virtual and medium-throughput screening produced NVP-AUY922, a well-tolerated Hsp90 inhibitor that progressed into global phase II trials.
Timeline Phase I entry 2007 to clinical proof of concept, April 2011.Outcome Clinical proof of concept, April 2011. -
Bcl-2 phase I clinical candidate
Structure-guided design produced S55746, an orally bioavailable and Bcl-2-selective inhibitor that spares platelets and reached phase I.
Outcome Phase I clinical candidate with a clean selectivity and tolerability profile. -
Mcl-1 in vivo active inhibitor
An NMR fragment screen and structure-guided design produced S63845, a specific, high-affinity Mcl-1 inhibitor with single-agent anti-tumour activity in vivo.
Outcome In vivo active inhibitor of a target long considered difficult to drug
Start your own success story
We’d love to hear from you! Head to our contact page to get started.