2023 Small Molecule Approvals! @drughuntersite A lot of fascinating firsts in 2023 including: -The first FDA-approved oral ER degrader -The first FDA-approved reversible BTK inhibitor -The first FDA-approved gamma-secretase inhibitor (not in Alzheimer’s!) -A reversible covalent, brain-penetrant Nrf2 activator -The first drug derived from mRNA display screening for macrocyclic peptides -The first PI3K inhibitor with a first approval outside oncology -A factor B-targeting Breakthrough Therapy for paroxysmal nocturnal hemoglobinuria -The first intranasal CGRP antagonist for fast-acting migraine treatment Full Open Access article + hi-res poster here:

Why Are VAV1 Degraders Such a Big Deal? Earlier this week, Novartis signed a deal for $150M upfront, up to $2.1B, with Monte Rosa Therapeutics. Drug Hunter scientists highlighted VAV1 patents earlier in the year and noted this program from a conference this summer (see link). Scientifically the program is notable as it suggests that CRBN E3-ligase-based degraders, which have traditionally been considered the most "drug-like" degrader category, can be applied to target proteins like VAV1 which do not have a canonical "G-loop" domain degron that CRBN recognizes. Expanding the scope of CRBN-based degraders has been of significant interest in the targeted protein degradation space and this clinical program suggests more is to come. Monte Rosa's VAV1 degraders appear to be exquisitely selective and orally efficacious in preclinical immunology models. The clinical development of VAV1 in healthy volunteers and immune-mediated disorders is notable given the high bar for safety in these areas, and the clinical history of imide-based degraders. Make sure your team has Drug Hunter access so you can catch these things well before they're published or seen in the news:

RT @drughunter_com: Check out the key SAR observations that led to the invention of this orally bioavailable PROTAC, its performance in a t…

RT @drughunter_com: A CNS-Penetrant ARα2C Antagonist Demonstrating Efficacy in Preclinical Obstructive Sleep Apnea Models |

RT @drughuntersite: An Oral Small Molecule PCSK9 Inhibitor with Remarkable Bioavailability | As part of our ACS Fa…

RT @drughuntersite: A Potential Best-in-Class HIF-2α Inhibitor Disclosed by Arcus | From the ACS Fall 2024 first-t…

RT @drughuntersite: We are thrilled to welcome Dr. Nicholas A. Meanwell, FRSC to the Drug Hunter Scientific Advisory Board! Dr. Meanwell i…

RT @drughuntersite: We are excited to welcome Dr. Dean Brown to the Drug Hunter Scientific Advisory Board! Dr. Brown brings over 25 years…

RT @drughuntersite: Targeting the “Impossible” Asp12 of KRAS(G12D)(ON) with an Aziridine-Containing Tri-complex |

@xinchen_w @RLCscienceboss @endpts @pablolubroth @HummingbirdVC Congrats @xinchen_w !

@pwk2013 🤣 was just waiting to hear it from you @pwk2013

@johnpoverington Wow!!

On Scaling Mentorship On the drive up to Seattle for the National Med Chem Symposium, I remembered some moments from nearly ten years ago when I was proposing some of my first compounds to synthesize. We were trying to improve the PK of a lead, and I brought my then-manager a list of several targets with hydroxyl groups all over the place, hoping to impress her with my initiative in designing my own targets. I had already placed orders for the building blocks (with her budget) and was ready to show her how quickly I could get these things done. Having just gotten out of grad school, I thought these were great ideas, since natural products have plenty of hydroxyl groups, and hydroxyl groups can make lots of hydrogen bonds, which could make them bind more tightly to our protein of interest... right? Needless to say I was disappointed by her muted reaction, which was the quiet "hmm" many managers have when they think their reports' ideas are dumb but are too polite to say so 🤣 I can't remember what she said exactly, but it was something along the lines of, "you should consider prioritizing your compounds based on what problems you think they're going to solve." I took the hint and decided against making my little monstrosities, which likely saved me a few weeks in the lab and our company a lot of money (though not all of it, since I'd already bought the starting materials...). I tend to be pretty action-oriented, and the reflection was a nice reminder that sometimes it's better to pause and really think through what actions we're going to take next, and why. A key role of a manager is to help their reports prioritize their work, and provide them with the knowledge and context they need to ultimately make great decision on their own. A challenge that I'm sure many managers find though, is that your ability to provide mentorship doesn't scale with the size of your team. While we would all love to be able to whiteboard ideas with our team members every day, once you have 8, 15, 25 people in your organization, it's physically impossible to give and get the facetime everyone needs. One of the reasons Drug Hunter (@drughuntersite) exists is to help scientists grow their knowledge on their own in the limited time they have, without needing to rely solely on the advice of more experienced colleagues whose time is also limited. I hope it helps other scientists at all career stages to find and apply the knowledge you need to solve your drug discovery problems, without needing to first embarass yourself in front of your manager like me :) Would love to hear how you've seen mentorship and knowledge transfer scaled across teams.

Sources for the stats: [Math on the 30 seconds thing: about 500k minutes in a year, over 1M papers added a year]

@cdsouthan I'm seeing $17-18k/user/yr for Scifinder, $7k-$15k/user/yr for Reaxys, $35-$50k for Cortellis, just curious if others are in the same ballpark or if there is variability (and based on what)

RT @drughuntersite: Molecules of the Month – May 2024 | Read the full article to find out what compounds made our…

Really nice explanation of where the target came from, the rationale, and key problems solved with this deceptively simple looking molecule!

RT @drughuntersite: Cerevance’s CNS-Penetrant KCNK13 Inhibitor Targets Brain-Specific NLRP3-Inflammasome Blockade |