Acqui-hire

Peptides are the poor person’s pharmaceuticals.

GLP-1 agonists didn’t show that peptides are the future. They proved the GLP-1 biology was an amazing opportunity and worth re-engineering into a small molecules.

Episode #2: Geron Podcast Episode · Approved · 13 March · 2h 22m

Fascinating story that ends in a cancer drug.

podcasts.apple.com/au/podcast/a...

N-Alkyl and N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabetic mellitus complications, and cerebrovascular disorders. As part of an internal program to develop orally bioavailable small-molecule pKal inhibitors, we report lead optimization efforts within the spirocarbamate scaffold, highlighting a structure-based drug design strategy to engineer hydrogen bond interactions with N-benzyl aminopyrazoles. Additionally, mitigation of time-dependent inhibition (TDI) liability and optimization of the overall profile were achieved through a two-pronged strategy: (1) incorporating increased Fsp3 modifications via N-alkylation and (2) leveraging torsional strain in N-aryl analogs.

A completey novel series of protease inhibitors from my time at Merck

pubs.acs.org/doi/10.1021/...

Gate Bioscience: Slamming the door on disease 🇺🇸 Gate Bioscience: Revolutionary 'molecular gate' drugs that act like cellular bouncers, blocking disease-causing proteins and unlocking groundbreaking treatments for previously untreatable condition...

hellyeah.xyz/p/gatebiosci...

Orthosteric

Machine Learning-Assisted Iterative Screening for Efficient Detection of Drug Discovery Starting Points High-throughput screening (HTS) remains central to small molecule lead discovery, but increasing assay complexity challenges the screening of large compound libraries. While retrospective studies have...

Here’s where I think AI is going to rapidly impact in drug discovery.

In this awesome paper from Roche they screen ~6% of a 2-million-compound library, and recover ~43% of all hits found in a full brute-force HTS, including essentially all the hit series.

pubs.acs.org/doi/10.1021/...

I started doing photonics and changes to medchem. Lasers are cool but making a medicine motivates me more.

Just looked it up. It seems to be especially sensitive to air. Apparently the blister packs for rinvoq are more resistant to moisture in the air.

What a year for biotech

I had no idea that was a requirement/recommendation.

I was asking someone about their GLP-1 use and they said they would prefer a weekly injection to a daily tablet. I’d prefer the tablet too TBH

Wegovy began as a diabetes drug and became a weight-loss breakthrough.

JAK inhibitors were originally designed for cancer, now for hairloss.

Cosmetic uses expand capital and demand and the science bleeds back into medicine.

Net gain.

Merry Christmas from Australia

Opioid receptor agonists take advantage of new understanding of GPCR biology Tool compounds separate pain relief from breathing suppression in mice

Researchers recently announced an advance in pharmacologists’ long-term goal to make a compound that could preserve the pain relief but ditch the undesirable side effects. cen.acs.org/biological-c... #chemsky 🧪

Wow, exciting convergence of chem bio technologies in this paper! 🤯

Structural basis of l-tryptophan-dependent inhibition of release factor 2 by the TnaC arrest peptide - PubMed In Escherichia coli, elevated levels of free l-tryptophan (l-Trp) promote translational arrest of the TnaC peptide by inhibiting its termination. However, the mechanism by which translation-termination by the UGA-specific decoding release factor 2 (RF2) is inhibited at the UGA stop codon of stalled …

The cryo-EM structure of a TnaC–ribosome complex shows how L-tryptophan stalls translation via a sequence-specific pocket in the exit tunnel (pubmed.ncbi.nlm.nih.gov/34403461) 
This is in prokaryotes but I’d bet the mechanism exists in eukaryotes.
#biotech #drugdiscovery #cryoEM #blueskybiotech

#blueskybiotech

OK this is now in the useable realm. Gemini beats chatGPT at schematic diagrams.

Great year for rare disease drugs

If it’s PROTAC linkerology sure, you can be relatively confident of the mechanism, but if it’s a glue or HTS library it’s tougher.

I think D2B is particularly challenging for degrader read-outs. The problem is that there are many mechanisms that can lead to reduced protein level, both direct and indirect. Careful controls and validations experiments need to be run which can compromise the efficiency gains of D2B.

Great news from Gate Bio! This Series B validates our differentiated approach: turning the cell’s single protein exit channel into a precision therapeutic target.

www.gatebio.com/gate-bioscie...

When are all the US scientists moving to Australia?

That new name…Genetix…wow

If someone argues that living “in nature” is inherently healthier, cats and dogs provide a counterexample: they clearly live longer, on average, when removed from “natural” conditions.

So sad

You’ve got to be kidding - I’m good thanks

Let’s Go!!