Target-guided synthesis, in which a protein templates the formation of its own inhibitor, is a concept first proposed decades ago. There are roughly two flavors. Dynamic combinatorial chemistry (DCC) involves reversible formation of the product, and we wrote in 2017 about some of the challenges. Kinetic target-guided synthesis (KTGS) involves irreversible chemistry, for which the options are limited. The classical click chemistry azide-alkyne cycloaddition is so slow that reactions usually take days, which can be a problem for delicate proteins. A recent (open-access) paper in Angew. Chem. Int ..read more

The name herpes makes most people think of painful ulcers in the mouth, or worse. But herpesviruses are actually a family of viruses that can also cause chicken pox, mononucleosis, and other diseases. Some 95% of adults are infected by at least one type of herpesvirus, and these can become deadly if people become immunocompromised, such as during an organ transplant. A drug that would inhibit all forms of herpesviruses would be useful, and the first steps are described in a recent ACS Med. Chem. Lett. paper by Michael Plotkin and colleagues at Merck.   The details of the primary screen ar ..read more

With crystal structures of protein-ligand interactions becoming increasingly accessible, it is easy to forget that proteins do not exist as the static structures seen on page or screen. Indeed, back in 2018 we quoted Karplus quoting Feynman that “everything that living things do can be understood in terms of the jiggling and wiggling of atoms,” and even the smallest proteins have lots of atoms. In an open-access paper published in Proc. Nat. Acad. Sci. USA earlier this year, Heike Schönherr, David Shaw, and collaborators at Relay Therapeutics, D.E Shaw Research, Pharmaron, and Columbia Univers ..read more

The protein β-glucocerebrosidase, also called GCase and GBA, is a lysosomal enzyme that cleaves glucosylceramide. People with inactivating mutations in both copies of GCase develop Gaucher’s Disease, which can be treated with a recombinant form of GCase. Heterozygous mutations increase risk for Parkinson’s Disease and for dementia with Lewy bodies, and though the mechanism is unclear, stabilizing the enzyme and/or boosting activity of residual GCase might help. This approach is described in a recent J. Med. Chem. paper by Nick Palmer and colleagues at Astex Pharmaceuticals.   The research ..read more

Back in 2017 we observed with characteristic subtlety that “heavy metals suck.” That post described a hit-finding campaign which foundered when the apparent activity of the fragments turned out to be due to contaminating zinc. A new paper in J. Med. Chem. by Thomas Gerstberger, Peter Ettmayer, and colleagues at Boehringer Ingelheim (BI) describes a similar story, along with suggestions of how to avoid being misled.   BI had a collaboration with FORMA Therapeutics that entailed screening roughly 1.7 million compounds against ten targets using biochemical and cell-based assays. The effort r ..read more

Well that’s an acronym soup! SAR by NMR was the first practical fragment-finding method, and over the years Practical Fragments has covered lots of other techniques. Small-angle X-ray scattering, or SAXS, has not been among them. As the name suggests, this technique uses X-rays, typically produced at a synchrotron. However, unlike conventional crystallography, it doesn’t require crystalline material. Instead, proteins in solution are analyzed to provide information on their size and shape. The resolution is too low to assess small molecule binding, but suitable for observing dimerization or ch ..read more

The year is half-way done, and we've seen some great events; I'll share my thoughts on FBDD Down Under 2024 next week. Boston is where it's at in the second half of 2024, and it's not too soon to start planning for 2025. September 22-25: After a six year hiatus, FBLD 2024 will be held in Boston. This will mark the eighth in an illustrious series of conferences organized by scientists for scientists. You can read impressions of FBLD 2018, FBLD 2016, FBLD 2014, FBLD 2012, FBLD 2010, and FBLD 2009. Early-bird registration ends August 12, so don't delay!   September 30 to ..read more

Three years ago we described the discovery of LYS006, an inhibitor of leukotriene A4 hydrolase (LTA4H) from Novartis currently in phase 2 clinical trials. Companies often pursue multiple chemical series for important targets, and in a recent J. Med. Chem. paper Gebhard Thoma and colleagues describe another fragment-derived lead against LTA4H.   A biochemical high-throughput screen yielded compound 2, which is quite potent for a fragment-sized molecule. However, despite good ligand efficiency, the LipE (or LLE) was less impressive due to the high lipophilicity of the fragment. (Note that t ..read more

As many of us know all too well, traditional methods to treat cancer often result in severe and even intolerable side effects. An emerging, gentler approach is based on synthetic lethality: targeting a protein that is essential only in certain cancer cells but not in normal cells. One prominent target is MAT2a, one of two human methionine adenosyltransferases. We’ve written previously about AG-270, a fragment-derived MAT2a inhibitor that entered the clinic. AstraZeneca has also pursued this target, as we discussed here. In a new J. Med. Chem. paper, Stephen Atkinson, Sharan Bagal, and their As ..read more

Practical Fragments has periodically written about protein tyrosine phosphatases (PTPs), which remove phosphate moieties from tyrosine side chains in proteins. Despite decades of attention, progress towards selective inhibitors has been slow due to both the similar active sites and their highly charged nature. A new paper in J. Med. Chem. by Zhong-Yin Zhang and colleagues provides some hope.   The researchers were interested in CDC14 phosphatases, so-called dual-specificity phosphatases that can dephosphorylate phosphoserine and phosphothreonine in addition to phosphotyrosine. Two members ..read more