Hope everyone is having a great US Thanksgiving week. This month’s update features quite a few contributions from international companies, including three from Bayer in Germany, a double soft drug from Leo Pharma in Denmark, and others from sites in Poland, Belgium, Spain, China, and India....

This was a loaded month for pioneering drug discovery programs! Among the highlights are a reversible-covalent inhibitor from Novartis, the hotly followed SHP2 inhibitor from Novartis, several innovative compounds from Pfizer including an oral GLP-1R agonist with a cryo-EM structure, a liver-targeted ACC inhibitor, and an oral KHK inhibitor. Remarkably, half of the molecules are negatively charged or pro-drugs of anions, and several have oral bioavailability beyond what a chemist 20 years ago would have thought probable. Most of these don’t look like they would be low-clearance, high bioavaila...

Plenty of eye-opening material was published this August! Among this month’s highlights are a small molecule with twice-a-year dosing from Gilead, a non-classical C-H—O hydrogen-bonding kinase inhibitor from Pfizer, an E1 ligase inhibitor with a cool substrate-assisted covalent mechanism from Takeda, and some STING agonists with well-tolerated oral activity and fascinating mechanisms from Merck and TSRI/Calibr. Links to the articles and more discussion on specific molecules below....

Many more modalities, mechanisms, screening strategies, and interesting chemical motifs appeared from the drug discovery community in July. This time we have a compound from a DNA-encoded library screen, some compounds derived from phenotypic screens, and a starting point identified from a high-throughput mass screen. We also have the first cryo-EM structure featured this year from the GNF team at Novartis, and a co-crystal structure with a normally membrane-bound protein thanks to Sosei Heptares. Links to the articles and more discussion on specific molecules below....

The drug discovery community kicked off the summer with a lot of very interesting molecules published in June. After ~50 molecular highlights so far this year, you’d think we’ve seen it all, but there were again numerous fascinating chemical motifs, molecular mechanisms, and biological observations disclosed last month. In this group are some natural-product inspired molecules, two metal-binding molecules (including a drug that binds its target via its ketone hydrate, something I had not seen before!), two transcription factor modulators, a molecular glue degrader, a receptor tetramerizer, and...

Here’s May’s round-up of small molecule highlights, with comments and links to articles below. There was a lot of diversity among targets last month, although there were surprisingly few structure-based campaigns disclosed. Plenty of interesting biology and chemical structures to consider!...

April 2020 was another great month for drug discovery publications, with several interesting first disclosures of clinical candidates and a variety of uncommon chemical motifs that will pique most chemists’ interest. Here’s a visual summary of the molecules, with some comments and links to the articles below:...

It's hard not to think about infectious diseases at the moment, but it's a great time to review the drug discovery literature. One area of drug discovery that has deep roots in infectious disease research is targeted covalent inhibition. Targeted covalent inhibitors form covalent bonds with discrete targets (as opposed to [...]

With the all the newsflow on drug re-purposing for the coronavirus, it’s easy to overlook all the interesting drug discovery articles that have been published in March. A summary of some of the most interesting compounds that appeared online this month appears below, and links to the original articles are at the bottom. Two molecules with degrader mechanisms that demonstrated compelling in vivo activity made this month’s list, and a flurry of excellent molecules intended for hot (or once hot) oncology targets appeared as well....

Of the 2019 biotech IPOs on the major US exchanges, there were 24 companies focused on developing non-small molecule drugs, about the same number as those developing small molecule drugs . Here’s a list of the companies (by market cap at IPO) along with a short summary of the key concepts for each company's main programs. *International [...]

At the time of this writing Kim Huard was one of Genentech’s Senior Scientists, and has spent a decade looking for new medicines.  She spent eight years at Pfizer at the Groton and Cambridge sites before joining us in California. She's currently a Director in the Discovery Chemistry department leading teams of scientists in pursuit of new [...]

Of the 2019 biotech IPOs on the major US exchanges, 25 companies are focused on discovering and developing small molecule drugs. Here's a list of the companies (by market cap at IPO, top to bottom) along with the main mechanisms of action of the lead molecules and other publicly disclosed targets. The largest company by market cap. at the [...]

This article introduces the Topliss tree and Topliss schemes for analog synthesis, illustrates when they might be useful, and provides easy-to-use posters or "cheat sheets" of the original schemes. By Christian Kuttruff Why are the Topliss Tree and Topliss Schemes Useful? Imagine you’re on a new project that has just conducted a chemical [...]

A lot of very interesting drug discovery campaigns have already been published online this year. A summary of some of the resulting small molecules that I found most interesting appears below, including several clinical candidates and many fit-for-purpose biological tool compounds to assess efficacy and toxicity. Grab a coffee and use this post as a starting point in getting caught up on the literature! Links to the original articles below....

This post briefly introduces chimeric molecules and companies working on them, contains a list of 10 recent “hot” papers in this field, and some predictions for where chimeras might head. It’s Chinese New Year time, which means a significant part of the global biopharma supply chain has ground to a halt, due to our colleagues and suppliers in [...]

or, How I Learned to Stop Worrying and Love My Own Definition. Recently I posted on “biologic drugs” which were approved in 2019 . All was well in my little scientific universe, until I received this in an email: “You recently reported "14 novel biologic drugs," referring to 'novel' biopharmaceuticals approved CDER. But, … You also include [...]

This article explains what LogD is, why LogD (or LogP) is important in drug discovery, rookie mistakes in drug discovery that come from overlooking LogD or LogP, and contains a LogD reference poster that shows the estimated amount of potency attributable to lipophilicity considerations alone. By Dennis Hu Jump to Cheat Sheet Lipophilicity is [...]

2019 was another big year for novel drug approvals (48 in total) though it wasn't the record year of 2018 (with 59). The overall explosion in biologic drugs / non-small molecule modalities continued with year with 14 novel biologic drugs, including 3 monoclonal antibodies, a recombinant fusion protein (Reblozyl), 3 ADCs, an siRNA drug [...]