While SNRIs and selective serotonin reuptake inhibitors (SSRIs) have been hugely successful in treating major depressive disorder (MDD), many patients remain resistant to treatment or do not experience full symptom relief. The majority of current treatments for MDD increase levels of synaptic serotonin and/or norepinephrine by inhibiting their reuptake transporters SERT and NET, respectively.

LRRK2 has been a hotly pursued drug target for Parkinson’s Disease based on human genetics. Clinical advancement of LRRK2 inhibitors was initially stalled by concerns about on-target lung findings in primates, but these were ameliorated by a Merck/Genentech/Pfizer/MJFF study showing that these lung changes were reversible, and Biogen/Denali has currently a small molecule (BIIB122/DNL151) in Ph. II (NCT05348785) after demonstrating safety and CNS exposure in 145 healthy patients in Ph. I (NCT04557800)

The First Disclosures sessions at the 2023 ACS Fall Meeting in San Francisco, organized by Nikki Goodwin, presented a variety of new orally available small molecules. The standing room-only sessions were so highly attended that many attendees were unfortunately kicked out due to the fire code.

To help drug discovery professionals get the most out of your trip to ACS San Francisco 2023, we compiled a table of sessions that are likely to be of high interest to industry scientists here.

This month features big announcements from Biogen on their acquisition of Reata and their Nrf2 activator for Friedreich’s ataxia and from BridgeBio on their TTR stabilizer with positive Ph. III data for their ATTR-CM treatment. A pair of KRAS inhibitors from Chugai (macrocycle) and AstraZeneca (brain-penetrant) also makes the list for their notable pharmacology. Other notable molecules from July include Aelis Farma’s Ph. IIb CB1 inhibitor, Boehringer Ingelheim’s Ph. II/III MDM2 PPI, and Janssen’s Ph. II P2X7R inhibitor. We’ll have more detailed case studies on these molecules coming soon, but...

TAK-994 is an oral, selective OX2R agonist developed by Takeda for the treatment of narcolepsy type 1 (with cataplexy) and type 2 (without cataplexy). The molecule follows Takeda’s previous clinical molecule, TAK-925 (danavorexton), which was the first OX2R agonist to be tested in people with NT1 but had poor oral bioavailability and was administered intravenously in the clinic.

Ziretaxestat, an oral autotaxin (ATX) inhibitor originated by Galapagos, once garnered excitement as the first molecule to complete a Ph. III clinical program in idiopathic pulmonary fibrosis since the approvals of nintedanib and pirfenidone. Following the disappointing clinical data and discontinuation of the molecule, this annotation revisits ziritaxestat in the context of other inhibitors, recaps the therapeutic hypothesis and how it was discovered, summarizes notable molecular properties for drug discovery scientists, and discusses what happened and what’s next.

Targeted Protein Degradation (TPD) allows for elimination, rather than inhibition, of proteins by exploiting cells’ own protein clearance mechanisms. While traditional inhibitors can be very effective at preventing a protein from undertaking a particular function, blocking protein activity...

A diaziridine-based tumor-activated prodrug for AKR1C3-expressing cancers from a defunct Bay Area biotech. OBI-3424 (formerly TH-3424) is a tumor-activated prodrug in Ph. II that releases DNA-crosslinking diaziridine phosphamide (remniscent of thioTEPA) upon activation by the NAD(P)H-dependent aldoketoreductase, AKR1C3, which is differentially expressed in many cancers. The molecule was originated at...

PF-07054894 is a potential first-in-class, oral Ph. I clinical candidate targeting the chemokine receptor CCR6 for ulcerative colitis (NCT05549323). Several companies have pursued antibodies and small molecules targeting CCR6 or its endogenous ligand, CCL20 (e.g. GSK3050002) for immunological conditions including other preclinical squaramides (e.g. Galderma, Allergan, ChemoCentryx) and other series (e.g. Takeda), but PF-07054894 appears to be the first selective CCR6 antagonist to enter clinical development.

The RAS proteins, KRAS4A, KRAS4B, HRAS, and NRAS control diverse cellular processes, and gain-of-function mutations in RAS genes are found in ~25% of cancers in humans, with KRAS mutations accounting for up to 85% of RAS mutations across cancers. While KRAS^G12C has been successfully targeted by approved drugs sotorasib and adagrasib and numerous candidates [...]

In Wednesday’s Flash Talk webinar, we covered recent highlights in targeted protein degradation, with lots of great questions from the audience. The webinar and recording are available below to everyone thanks to our sponsor, Revvity Signals, and the slides are available for download to Premium members at the bottom.

This article compiles recent high-profile clinical readouts and related news with small molecules of general interest and structures where they are available. Targets and indications discussed in this article include BTK for MS, Axl, TYRO3, and Mer for oncology, HIF prolyl-hydroxylase in anemia, ET/AT in nephrology, a JAK2 inhibitor for myelofibrosis, and THR-beta in NASH. [...]

This article highlights million-dollar molecules that were recently in the news with related patent applications that give clues to their structures and properties. This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targeted protein degradation researchers, brain-penetrant HER2 and ROCK2 inhibitors, and MDM2 degraders.

CFT1946 from C4 Therapeutics is a potent, selective, and orally bioavailable bifunctional degrader of mutant BRAF in Ph. I/II for the treatment of BRAF-driven solid tumors, alone and in combo with a MEK1/2 inhibitor (trametinib) (NCT05668585). BRAF-V600X is clinically validated with approved drugs (e.g. vemurafenib), but traditional inhibitors face challenges in selectivity over wildtype BRAF and can cause paradoxical RAF activation. [...]

Camlipixant is an orally administered antagonist of the ATP-sensing P2X3 homotrimeric receptor ion channel, originated by AstraZeneca AB and assigned to the Canadian NEOMED Institute (now adMare), and developed by BELLUS Health (Canada), for the treatment of chronic cough. Chronic cough remains difficult to treat – the last FDA-approved anti-tussive, dextromethorphan, was first approved in 1958 and has demonstrated limited clinical efficacy.

Small molecule drugs make up most of the drugs we take conveniently as pills, including painkillers like ibuprofen (Advil), antibiotics like penicillin and amoxicillin, or cholesterol-lowering drugs like atorvastatin (Lipitor). The biotechnology revolution allowed scientists to create drugs through genetic engineering and related biological processes, creating a new category of drugs known as “biologics.”...

A second-generation AR bifunctional degrader for drug-resistant prostate cancer. ARV-766 is Arvinas’ second bifunctional CRL4 CRBN E3 ligase-based androgen receptor (AR) degrader to enter the clinic for the treatment of prostate cancer (PCa), after ARV-110 (bavdegalutamide) . The glutarimide recruiting element is notable as it is simpler than [...]