{"id":3210,"date":"2023-01-22T17:09:59","date_gmt":"2023-01-22T23:09:59","guid":{"rendered":"https:\/\/kermitmurray.com\/msblog\/?page_id=3210"},"modified":"2023-01-22T17:09:59","modified_gmt":"2023-01-22T23:09:59","slug":"science-in-the-pipeline","status":"publish","type":"page","link":"https:\/\/kermitmurray.com\/msblog\/links\/journal-feeds\/science-journals\/science-journal\/science-in-the-pipeline\/","title":{"rendered":"Science in the Pipeline"},"content":{"rendered":"\n<div class=\"wp-block-caxton-grid relative\"><div class=\"absolute absolute--fill\"><div class=\"absolute absolute--fill cover bg-center\" style=\"background-color:;background-image:linear-gradient( );\"><\/div><div class=\"absolute absolute--fill\" style=\"background-color:;background-image:linear-gradient( );opacity:1;\"><\/div><\/div><div class=\"relative caxton-columns caxton-grid-block\" style=\"padding-top:0;padding-left:0;padding-bottom:0;padding-right:0;grid-template-columns:repeat(12, 1fr)\" data-tablet-css=\"padding-left:em;padding-right:em;\" data-mobile-css=\"padding-left:em;padding-right:em;\">\n<div class=\"wp-block-caxton-section relative\" style=\"grid-area:span 1\/span 8\"><div class=\"absolute absolute--fill\"><div class=\"absolute absolute--fill cover bg-center\" style=\"background-color:;background-image:linear-gradient( );\"><\/div><div class=\"absolute absolute--fill\" style=\"background-color:;background-image:linear-gradient( );opacity:1;\"><\/div><\/div><div class=\"relative caxton-section-block\" style=\"padding-top:5px;padding-left:5px;padding-bottom:5px;padding-right:5px\" data-mobile-css=\"padding-left:1em;padding-right:1em;\" data-tablet-css=\"padding-left:1em;padding-right:1em;\">\n<p><strong><a href=\"https:\/\/www.science.org\/content\/page\/email-alerts-and-rss-feeds\" target=\"_blank\" rel=\"noreferrer noopener\">Journal Home<\/a><\/strong><\/p>\n<\/div><\/div>\n\n\n\n<div class=\"wp-block-caxton-section relative\" style=\"grid-area:span 1\/span 4\"><div class=\"absolute absolute--fill\"><div class=\"absolute absolute--fill cover bg-center\" style=\"background-color:;background-image:linear-gradient( );\"><\/div><div class=\"absolute absolute--fill\" style=\"background-color:;background-image:linear-gradient( );opacity:1;\"><\/div><\/div><div class=\"relative caxton-section-block\" style=\"padding-top:5px;padding-left:5px;padding-bottom:5px;padding-right:5px\" data-mobile-css=\"padding-left:1em;padding-right:1em;\" data-tablet-css=\"padding-left:1em;padding-right:1em;\">\n<p><strong><a href=\"https:\/\/www.science.org\/blogs\/pipeline\/feed\" target=\"_blank\" rel=\"noreferrer noopener\">RSS<\/a><\/strong><\/p>\n<\/div><\/div>\n<\/div><\/div>\n\n\n<ul class=\"has-dates has-authors has-excerpts wp-block-rss\"><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/futuristic-synthesis-indeed'>A Futuristic Synthesis Indeed<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I definitely need to cover this recent work from Merck, because (1) it\u2019s very interesting scientifically and (2) it has over 130 authors on the paper (!) It details the industrial synthesis of enlicitide, which is a beast of a macrocyclic peptide (see below!) Just looking at the structure tells you that this must be a ferociously active molecule with huge commercial potential, because there is just no way that anyone is going to make this on scale &#8211; or [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/what-success-can-look-darn-it'>What Success Can Look Like, Darn It<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I wrote here last year about the clinical trial results for the first \u201cbifunctional degrader\u201d molecule to make it that far, vepdegestrant from Arvinas and Pfizer. That post will send you to some background information about this class of molecule, but suffice it to say that they represent a completely new mode of action (destruction of a target protein in the living cell as opposed to chemical inhibition of it). As such, this program has been watched closely, and the [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/more-vague-more-useful'>More Vague, But More Useful<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I think that many synthetic organic chemists will be able to relate to the approach described in this paper, on software-aided route design. Its authors are trying to make such software take a viewpoint from higher over the synthesis, rather than working out every reaction. As noted in this commentary, for larger molecules that can leave you with a forest of rather-similar routes that differ in choice of protecting groups, relative oxidation states, order of reactions and other details that [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/those-pesky-post-translational-modifications'>Those Pesky Post Translational Modifications<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I\u2019ve written here many times about various post-translational protein modifications. That\u2019s a huge field of study, because it has become more and more clear over the years that it\u2019s not so much that living cells have huge numbers of different protein sequences in them (although they have plenty!) it\u2019s that every protein seems to be modifiable by a long list of add-ons. These include (but are absolutely guaranteed not to be limited to!) phosphorylation, ubiquitination, farnesylation, glycosylation, acetylation, palmitoylation and [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/latest-news-vaccine-obstruction'>The Latest News in Vaccine Obstruction<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Well, I know by now what happens when I bring up vaccines, but I\u2019m going to do it anyway because we have a lot of news. As many will have heard, news broke recently of several large-scale studies of safety for the coronavirus and shingles vaccines. Here\u2019s the New York Times on the story, and here\u2019s the Guardian. These were done by evaluating millions of patient records, and seem to have concluded that these vaccines are in fact safe, with [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/ubiquitin-rides-again'>Ubiquitin Rides Again<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">When appropriate I usually wait until the end of one of these posts to draw attention to the way that its subject dovetails (or not) with the current fashion for AI\/ML techniques. For one thing, I find it helpful to remember that really new results cannot generally be obtained by asking an LLM system that is trained on piles of existing text which it has blended and chopped and extruded back to you. That\u2019s because those new results were not [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/helium-and-strait-hormuz'>Helium and the Strait of Hormuz<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">OK, let\u2019s talk helium today. A while back I wrote about the Haber-Bosch process for making ammonia (and thus making nitrogen fertilizer), and how that was already being impacted by the then fresh and new Iran war. Well here we are in the first week of May, and urea prices can best be described as \u201chigh and choppy\u201d, jumping around (as does crude oil) on news of the war. Here\u2019s the freight-on-board futures price for the Middle East, and if [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/open-letter-jay-bhattacharya'>An Open Letter to Jay Bhattacharya<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Dear Dr. Bhattacharya: I write to inquire about your state of mind. That may seem an unusual request, but these are unusual times, and God knows you have been appointed to serve in an extremely unusual administration. As Director of the NIH (a post &#8211; let\u2019s be frank here &#8211; that for many years I\u2019m sure you never seriously imagined that you might hold) you have of course a great many responsibilities, facing not only your direct reports and employees, [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/fda-cracks-down-tavneos'>The FDA Cracks Down on Tavneos<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">We have quite a regulatory situation developing around a drug called avacopan (Tavneos), which is given to patients with a particular type of vaculitis. That\u2019s a complex disease area, and comes in several varieties, but a common theme in many of them is an autoimmune attack against various proteins found in neutrophils. The drug is an antagonist of the complement 5a receptor in the innate immune system, and it\u2019s given along with other immunosuppressants. It was developed recently by a [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/latest-synthetic-automation-proposal'>The Latest Synthetic Automation Proposal<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">This article (open access) is the latest in a long, long series of implementations of an idea that is very simple to state and very difficult to achieve. That is, what if we (1) had a set of machines that could run organic chemistry reactions for us, ones that (2) could also analyze how well these reactions worked (yield, purity and so on), and that (3) could then use some sort of software evaluation of the data to set up [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/no-heart-cancer-there-s-reason'>No Heart Cancer? There&#039;s a Reason<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Think about it: have you every heard of a case of heart cancer? It\u2019s very rare indeed, and why that\u2019s the case has been a longstanding puzzle. This new paper (here at Science) seems to have found a big piece of the answer, though. Cardiomyoctes are a rather special class of cell, but one of the fundamental things that make them special is that they are always in motion and under mechanical stress. If you raise them correctly in a [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/fluorines-reactive-handles-eh'>Fluorines As Reactive Handles, Eh?<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">You can put this one in the \u201creactions I never expected to see\u201d category, because it\u2019s a way to selectively functionalize aryl rings with multiple fluorines on them. And no, I don\u2019t mean \u201cfunctionalize at the carbon(s) that aren\u2019t fluorinated yet\u201d or even \u201ckick out the most likely SnAr leaving group fluorine\u201d. This is stepping and and replacing fluorines with H, D, alkyls or other aryls. The reason this looks so odd is that most of the time in organic [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/progress-against-pancreatic-cancer-part-one'>Progress Against Pancreatic Cancer, Part One<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">We have some really interesting progress in pancreatic cancer to talk about, both on the small-molecule and the mRNA vaccine fronts. Let\u2019s do the small-molecule ones first, because those were honestly more unexpected. So to lead off, Revolution Medicines announced at the AACR meeting in San Diego that their drug daraxonrasib showed strong efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). That is a very, very difficult to treat population &#8211; these people typically have only a few months [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/lyme-vaccines-past-and-possibly-future'>Lyme Vaccines, Past and Possibly Future<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Living in New England, we tend to get out into the yards, parks, and gardens this time of year because we\u2019ve pretty much had it with winter. Of course, winter hasn\u2019t always had it with us &#8211; we\u2019ve had frost here the last couple of mornings, so it\u2019s not exactly time to put the tomatos and cucumbers out there yet. But whenever the weather does start to warm up, so (unfortunately) does the threat of tick-borne diseases like Lyme. That [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/bizarre-viruses-indeed'>Bizarre Viruses Indeed<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Translation of mRNA into proteins is a nonstop, nonnegotiable process that is essential to the life of a cell, and it has acquired a *lot* of evolutionary tuning over the last few billion years. In critters like us with nuclei and other such organelles (the big happy club of eukaryotes, to which so many of my readers belong as G. K. Chesterton used to say), there\u2019s a very important protein complex called elF4F. That\u2019s short for \u201ceukaryotic initiation factor 4F&quot;, [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/anti-amyloid-antibodies-alzheimer-you-already-know'>Anti-Amyloid Antibodies for Alzheimer: You Already Know<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">This is not going to come as a surprise to readers of this site, because even if you don\u2019t agree with this contention you have certainly at least been exposed to it: the Cochrane Review folks have examined the clinical evidence for anti-amyloid antibodies as therapies for Alzheimer\u2019s and found, well. . .you know what they found: The effect of amyloid\u2010beta\u2010targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/antimalarial-drugs-stepping-each-other-s-toes'>Antimalarial Drugs Stepping On Each Other&#039;s Toes<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Artemisinin-based therapies are the absolute mainstay of malaria treatment the world over, so this new paper deserves attention. The drug is often given in combination with the older aminoquinoline agents like choloroquine, piperaquine, and amodiaquine, but the authors here make a strong case that this is actually counterproductive. As the paper notes, heme is central to the mechanism of action for both kinds of drugs. The aminoquinolines bind to it and affect heme homeostasis, and may well product toxic adducts [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/answers-and-reasons-and-knowing-and-thinking'>Answers and Reasons and Knowing and Thinking<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I spent a day at Williams College last week, which I enjoyed very much, and I found a part of my lecture there overlapping with a big topic in undergraduate education. I have a section in several of my talks where I speak about AlphaFold-type machine learning and its implications for drug discovery, and that seemed to fit rather closely into concerns that many professors are having about the effect of AI systems on coursework and learning. I\u2019m sure that [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/predicting-antibody-binding-no-champagne-just-yet'>Predicting Antibody Binding: No Champagne Just Yet<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I often get asked what areas of drug discovery look most likely to bear AI-driven advances into the clinic, and my usual answer is \u201ctherapeutic antibodies\u201d. Thats because it\u2019s a protein-centric problem in the actual modeling, and we know quite a bit already about antibody structures (at least as compared to the much large wild-type protein structural landscape). And that\u2019s because antibodies themselves are a (relatively!) constrained space within that larger one, although don\u2019t let anyone tell you that it\u2019s [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/consider-selfish-ribosome'>Consider the Selfish Ribosome<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">If you look at cells dispassionately, one of the things that strikes is that man, do we ever have a lot of ribosomes. These are of course the protein-synthesis machines that are kept humming nonstop as RNA sequences are translated into protein sequences, and ribosomes themselves are structurally a mixture of proteins and some unusual RNA molecules all their own. The peptidyltransferase center (PTC) where the actual synthesis of new peptide bonds takes place is itself a flat-out ribozyme, an [&hellip;]<\/div><\/li><\/ul>\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity is-style-wide\"\/>\n\n\n\n<h4 class=\"wp-block-heading\">Related Journals<\/h4>\n\n\n<ul class=\"su-siblings\"><li class=\"page_item page-item-3212\"><a href=\"https:\/\/kermitmurray.com\/msblog\/links\/journal-feeds\/science-journals\/science-journal\/science-first-release\/\">Science First Release<\/a><\/li>\n<li class=\"page_item page-item-3208\"><a href=\"https:\/\/kermitmurray.com\/msblog\/links\/journal-feeds\/science-journals\/science-journal\/science-podcast\/\">Science Podcast<\/a><\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Related Journals<\/p>\n","protected":false},"author":1,"featured_media":3202,"parent":3204,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-3210","page","type-page","status-publish","has-post-thumbnail","hentry","entry"],"_links":{"self":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3210","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/comments?post=3210"}],"version-history":[{"count":1,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3210\/revisions"}],"predecessor-version":[{"id":3211,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3210\/revisions\/3211"}],"up":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3204"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/media\/3202"}],"wp:attachment":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/media?parent=3210"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}