Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.
Since targeted protein degradation is such a hot topic these days, this paper (which adds to the results obtained by this one) should get some interest. It’s a report of a detailed look at the kinetic behavior of several bifunctional degraders – and there’s a lot of kinetic behavior to look at. That’s because you’re l… Read More
The Cravatt group (in collaboration with partners from Harvard and Bristol-Myers Squibb) has a paper out on Chemrxiv that’s a followup to a 2017 paper of theirs which (I will freely admit) is one of my favorites. That was on taking fragment-sized compounds (and a slightly higher-MW collection), each labeled with a diazirene (for photoaffinity… Read More
Medicinal chemists spend the vast majority of their time targeting proteins. Enzyme active sites, receptors, allosteric sites, interfacial sites – it’s one protein after another, to the point that you can mentally assume that your compounds are going to be hitting the familiar landscape of backbone amide bonds, pi-interacting tryptophan… Read More
One would like to be able to reach into a cell and mess around with its functions in real time. Thanks to CRISPR and other gene-editing technologies, we can (more or less selectively) tweak individual genes, to a wide number of interesting effects. What if that gene just disappears? What if it gets expressed even more?… Read More
Here’s something that many of us don’t tend to think about when we think about enzymes: vibrational energy. But it’s long been thought that anisotropic vibrational energy transfer (VET) plays a role in both enzyme active sites and in things like coupling to allosteric sites. Getting a handle on that, though, has not been easy… Read More
Every “history of pharmaceuticals” article ever written probably mentions quinine, and well they should. (I certainly reserved an entry for it while writing my own chemical history book). It’s a classic example of a natural product drug, one that was not known to the classical Mediterranean world but was only appreciated by Europe… Read More
Microbiome, microbiome – you haven’t been able to turn around in this business the last few years without hitting some sort of story about the microbiome. It’s easy to roll your eyes and decide that it’s all hype, but that’s the thing: it really is important. It can’t be dismissed just because we don’t unde… Read More
Why do some proteins in a family prove very hard to target, while others bind a whole list of inhibitors? This paper takes a look at a particularly dramatic example in the kinase field. That’s a good place for studying such things, since there are a lot of kinases out there, and a lot of… Read More
An interesting feature of many proteins is a disordered region down at the carboxy end. The reason for this feature has been obscure: if there’s part of the protein that just spends its days flailing around uselessly, why go to the trouble of translating it? Many of these tails certainly seem to have no defined structural… Read More
3-bromopyruvate is an interesting and controversial compound. It’s been reported to be an active chemotherapy agent, apparently acting via covalent inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and subsequent metabolic effects via loss of pyruvate itself. Several years ago, you could come across numerous web pages touting it… Read More
