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 [...]

PDE4 inhibitors have shown promise in a range of pulmonary, dermatological and neurological diseases, but have been hampered by side effects including emesis and diarrhea . Difamilast , originated by Otsuka , recently approved for the treatment of atopic dermatitis [...]

Macrocyclic molecules, containing 12 or more atoms in a ring system, are increasingly prevalent in drug discovery, with over 67 macrocyclic drugs approved so far and several notable examples of clinical success highlighted on Drug Hunter recently, including MK-0616 , repotrectinib , and pacritinib . By imparting conformational restraint and [...]

The first non-ATP-competitive inhibitor of the long-pursued PI3Kδ kinase. Phosphatidylinositol-3-kinase (PI3K) has received intense attention as a drug target from the pharmaceutical industry due to its central role in cancer and involvement in other indications. As described in our recent overview of this area, numerous compounds have [...]

This article compiles 20+ recent small molecules of general interest in the news in April 2023, with structures where they are available. Capacity Bio’s MAS Receptor Agonists with $35M Raised for FIH Clinical Trials MAS modulator from WO2022165189 example 107 New start-up Capacity Bio backed by RA Capital, Insight Partners, and Remiges [...]

With the popular success of diabetes and weight-loss peptide drugs from Novo (e.g. semaglutide/Ozempic), this month features a pair of ultra-hot non-peptide oral GLP-1R modulators in clinical development. Other notable Molecules of the Month include vorasidenib, which demonstrated headline-generating efficacy in brain cancers, as well as controversial billion-dollar molecule atrasentan, the subject of a short-seller report by Muddy Waters. We’ll have more detailed case studies on these molecules coming soon, but in the meantime you can check out some recent articles about the following here: o...

The orally administered gepotidacin is a member of a novel class of type IIA topoisomerase inhibitors , also called novel bacterial topoisomerase inhibitors ( NBTIs ), for which the mode of action and binding mode with a topoisomerase was first disclosed in 2010 by [...]

BAY 1165747 (BAY-747) is a new, structurally distinct, soluble guanylate cyclase (sGC) stimulator with potential in the treatment of resistant hypertension . Identified through ultrahigh-throughput screening, it features an imidazo[1,2-a]pyridine core, distinct from the [...]

Indoleamine 2,3-dioxygenase 1 (IDO1) is an extrahepatic tryptophan-metabolizing enzyme which is believed to contribute to the evasion of the immune system by tumors , making it an attractive target for cancer immunotherapy, especially in combination with immune [...]

We couldn’t include everything in Molecules of the Month, but here’s a round-up of up of 16 additional molecules of potential interest that we didn’t have space for in April, including a highly selective caspase inhibitor from a non-catalytic cysteine, a GPR40 AgoPAM from BMS with activity on GLP-1, a few examples of both on- and off-target [...]

This “journal club” article highlights five recent articles of general interest to drug discovery scientists, including reviews on therapeutic areas of interest, principles and areas of medicinal chemistry and pharmacology, and a synthetic transformation worth keeping in mind. 1. A “Magic Chloro” Med. Chem. Review D. Chiodi and Y. Ishihara [...]

This article highlights six recent articles of interest in the field of targeted protein degradation including but not limited to potentially new ligases, recruiting motifs, and a discussion on the feasibility of CNS-penetrant degraders. 1. “Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings” [...]

Dian Su’s journey from chemistry and proteomics to the DMPK of drug conjugates Following a different path comes naturally to Dian Su, Senior Director of DMPK at Bicycle Therapeutics. From a childhood in a small village in China’s northeast Shandong province to her work examining the drug metabolism and pharmacokinetics (DMPK) of antibody-drug [...]

ACT-777991, an oral and insurmountable CXCR3 antagonist discovered by Idorsia (formerly Actelion), is under investigation for the treatment of Type 1 Diabetes (T1D). Despite the complex history of CXCR3 antagonists, ACT-777991 has shown promise with [...]

Finally, December’s molecule, the Novo Nordisk oral insulin analog OI338, is the first oral insulin to demonstrate similar outcomes to insulin glargine injection in a Ph. II clinical trial. The molecule has an ultralong PK profile (t1/2 = 70 h) due to the inclusion of an albumin-binding long-chain fatty acid. [...]

November’s molecule, the Chugai/Lilly GLP-1R agonist LY3502970, is a highly potent and selective, oral, biased partial agonist of the GLP-1R GPCR. GLP-1R agonists have been approved for many years now to treat Type II diabetes mellitus, due to their ability to stimulate insulin secretion in pancreatic beta-cells. [...]

October’s molecule, the Bayer hGnRH-R antagonist BAY 1214784 , is intended as an oral, once-daily treatment for uterine fibroids, a highly common problem in adult women that can lead to infertility. Existing treatments include hGnRH-R blockers which have undesirable side effects such as induction of menopausal symptoms due to their influence [...]

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progression of certain cancers. The Novartis team found that the FGFR4 protein has a high re-synthesis rate and therefore would require significant drug exposure to have a meaningful effect, so they deprioritized [...]