This article published in Nature describes a first-in-class METTL3 inhibitor for the treatment of acute Myeloid Leukaemia.
The publication covers:
Tags: Medicinal Chemistry, Oncology, Articles & Whitepapers, SBDD, crystallography, epigenetics
Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK
As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.
Tags: Antibacterial, Medicinal Chemistry, Articles & Whitepapers, ADME/DMPK, In vitro Biology, In vivo Pharmacology, Anti-Infectives, Antimicrobial resistance
The ‘core’ metabolome of the Bacteroidetes genus Chitinophaga was recently discovered to consist of only seven metabolites. A structural relationship in terms of shared lipid moieties among four of them was postulated. Here, structure elucidation and characterization via ultra-high resolution mass spectrometry (UHR-MS) and nuclear magnetic resonance (NMR) spectroscopy of those four lipids (two lipoamino acids (LAAs), two lysophosphatidylethanolamines (LPEs)), as well as several other undescribed LAAs and N-acyl amino acids (NAAAs), identified during isolation were carried out.
Tags: Medicinal Chemistry, Articles & Whitepapers, Anti-Infectives
Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK
The problems surrounding the economics of antibacterial drug development are well known, with the cost of simply keeping a product available for use now outstripping revenues from sales in many cases.
However, early R&D push incentives from organisations such as CARB-X and the new AMR Action Fund are keeping research going, while efforts continue to try to ensure the true value of novel antibiotics are recognised, spearheaded by the UK’s pilot of a subscription model for reimbursement of developers of new antibiotics
The challenges of running clinical trials sufficient for approval and securing adequate sales returns can affect scientific strategy, resulting in the targeting of only broad-spectrum agents most desired by clinicians. Through years of research, and discussions with members of the antibacterial research community, it became clear to me that the understandable focus on what both regulators and the market will currently support can be at odds with some of the most promising avenues in the science of antibacterial drug discovery. Narrow spectrum or even single pathogen agents may be of huge value in years to come, and from a scientific perspective, these compounds may be more readily accessible than broad-spectrum drugs.
As a medicinal chemist, my primary focus is on molecular design, and while there are many excellent reviews in the field, I felt that a perspective addressing how the many aspects of antibacterial drug discovery affect our design strategies would be a useful addition. I visualise any problems from the viewpoint of the antibiotic molecule, and consider the various challenges it must overcome to become a useful agent for clearing bacterial infections. In each case I consider how our knowledge should influence design strategies. While these principles are at the heart of our research at Evotec, I hope that sharing these ideas with the wider community will aid researchers in their work to address the growing threat of AMR.
Tags: Medicinal Chemistry, Blog, Anti-Infectives
Tags: Medicinal Chemistry, Respiratory, Articles & Whitepapers, In vitro Biology, Anti-Infectives
Tags: Medicinal Chemistry, Respiratory, Articles & Whitepapers, In vitro Biology, Anti-Infectives
Tags: Medicinal Chemistry, Evotec, Women's health, Immunology & Inflammation
Tags: Medicinal Chemistry, Women's health, Articles & Whitepapers, Hit & Target ID/Validation, Immunology & Inflammation
Tags: Medicinal Chemistry, Articles & Whitepapers, Immunology & Inflammation
Tags: Medicinal Chemistry, Respiratory, Articles & Whitepapers, Immunology & Inflammation