Spring 2017 Newsletter
Welcome to the Spring 2017 Newsletter from CompChem Solutions Limited.
Every so often huge strides are made in a particular therapeutic area. One recent example of this, which has employed quite extensive use of computational structure-based design approaches, is in the area of B-cell haematological oncology. Two newly approved drugs for CLL/SLL, ibrutinib & venetoclax, were both developed with the aid of structural design. We feature an article on these game-changing therapies, and invite scientists working in this field to propose new targets for future therapies. CompChem Solutions may be able to provide limited fee-free support for development of grant proposals in the haematological oncology area.
We’ve been beta-testing Cresset’s new Flare application, which now enables inclusion of proteins to Cresset’s unique field-based approach. Their User Group Meeting is only a few weeks ago so do attend if you’d like to learn more about Flare and their other recent innovations.
The next UK-QSAR meeting is approaching fast – we hope to see you there! Do register if you’re planning to attend as time is running out. And it’s nearly time for the CCG UGM too if you’re up for a trip to Copenhagen next month.
- Susan Boyd has recently co-authored a publication from Cancer Research Technology on “The development of potent inhibitors of the lysophospholipase autotaxin”
- We’ve been delighted to to take a first look at Cresset’s Flare software for modelling protein systems using their field-based approach. Further beta testing is now underway.
- If you need patent or chemical information searching services, do contact us!
- Do register for the UK-QSAR Meeting if you plan to attend! And please let us know if you’ve already registered but can no longer attend.
CompChem Solutions partners with Collaborative Drug Discovery
Susan M Boyd, CompChem Solutions Ltd
CompChem Solutions Ltd is delighted to have become an Advocate partner for Collaborative Drug Discovery (CDD). CDD offers a modern approach to research informatics, with their Vault application hosting a secure biological & chemical database platform which is simple to use and ideally positioned for use by small and large drug discovery teams alike. Their secure web-interfaced system includes tools for molecular visualisation, an ELN, a compound inventory as well as tools for logging compound activity and registering compounds, and is designed to support ready sharing of data across sites and between teams. Contact us for further information.
Structure-based design has helped change the landscape of B-cell targeted oncology
Susan M Boyd, CompChem Solutions Ltd
Until quite recently, the only therapies available to patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) were “traditional” chemotherapy approaches. These typically involve the use of a combination of alkylating agents, antibodies and sometimes T-cell/immunosupressants. However, the side effects of these treatments can be significant, their effects last for at best the medium term, and they may even precipitate unfavourable clonal changes in cells to predispose the patient to complications or even secondary cancers further down the line.
In 2013, the whole landscape of treatment for these B-cell cancers was revolutionised, with the FDA approval of ibrutinib. Ibrutininb, or Imbruvica, is an irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK), and instrumental in its development was the use of computationally-driven structure-based approaches to guide compound design (Pan et al, ChemMedChem, 2, 58-61, 2007). The drug sits in the ATP binding site of BTK, covalently bonding to C481. Initially a homology model of activated BTK was derived based on the unphosphorylated BTK structure 1K2P and the active structure of LCK kinase 1QPE.
From this the non-catalytic cysteine was identified and analogues synthesised and subsequently optimised, resulting in the final drug compound. The compound was FDA-approved for mantle cell lymphoma in 2013,then for specific forms of CLL/SLL in 2014. In the UK NICE finally approved its use for specific CLL/SLL patients at the end of 2016. Clinical trials have shown remarkable efficacy. The RESONATE trial demonstrated an over 90% response rate to ibrutinib compared with 25% rate in the standard treatment.
Following close on the heels of ibrutinib, apoptotic regulator BCL-2 inhibitor venetoclax (aka ABT-199) was designed based on the known BCL-Xl/BCL-2 inhibitor navitoclax. Navitoclax itself shows dose-limiting thrombocytopenia toxicity, and it was considered that this was likely due to its lack of selectivity towards BCL-Xl. Reverse engineering of navitoclax together with peptidomimetic design studies on other hot spot regions of the BCL-2 site were used to develop the BCL-2 selective compound venetoclax (Souers et al, Nature Medicine,19(2), 202-208, 2013).
It was approved for use in specific CLL/SLL patients by both the FDA & the EMA in 2016. It is still under consideration by NICE in the UK but has been approved for inclusion in the Early Access to Medicines Scheme (EAMS) and has shown an over 80% overall response rate in early clinical trials, whilst showing a highly favourable safety profile.
These drugs are true game changers in this field of oncology, and other so-called “pathway” therapeutics have also emerged, such as idelalisib. However, the future of treatment of B-cell cancers may well lie in the use of combination therapies, involving single or multiple small molecule agents combined with antibody use. Many clinical trials are ongoing and this is a truly exciting area of research. There has been some concern over reports that inhibitors of the PI3Kdelta pathway, including ibrutinib itself may themselves induce increased expression of activation-induced cytosine deaminase (AID) over the long term, which may lead to genomic instability and to development of lymphoma. Further studies are certainly needed to establish the level of resistance to these newer drugs, and to explore their long-term usage safety. There is still a very great need for alternative and/or improved therapies.
If you have a potential drug target which might be of use in future therapies B-cell malignancies, do get in touch. We may be able to provide limited support free of charge in terms of structural assessment of druggability of targets and to provide background information in support of grant applications.
The following meetings may be of interest to our readers:
CCG UGM & Conference (Europe), 16-19 May 2017, Copenhagen
Symposium on Streamlining Drug Discovery (Optibrium, BioSolveIT, Lhasa & Takeda), 18 May 2017, Cambridge
Cambridge Chemoinformatics Forum, 24 May, Cambridge
Cresset UGM, 29-30 June 2017, Cambridge
UK QSAR & Chemoinformatics Group Autumn 2017 Meeting, 29 September 2017, MIB, Manchester
SCI Epigenetics 2017, 7 September 2017, Windlesham, Surrey
19th RSC/SCI Cambridge MedChem Symposium, 10-13 September 2017, Churchill College, Cambridge
Some current jobs being advertised…….
Team Leader (CADD), Charles River Laboratories, Saffron Walden, Essex
Application Scientist, Chemical Computing Group Inc, Cambridge (UK) or Cologne (Germany)
Senior Scientific Consultant, Cresset Group, Litlington, Cambridge, UK
Product Manager (API), RSC, Cambridge, UK
Chem- and Bioinformatics Scientists, Software Engineers, Machine Learning Researchers, Benevolent.ai, London, UK