AZ13824374 (AstraZeneca) is an in vitro ATAD2 inhibitor. Reviewer and nominator Julien Lefranc says, “several ATAD2 probes have been published in the past (including GSK 8814, GSCK388, and BAY-850), but so far no compounds have reached clinical trials.” ATAD2 is a bromodomain-containing, chromatin-binding target that is overexpressed [...]

Context. AZD7648 (AstraZeneca) is an oral DNA-PK inhibitor. DNA-PK, ATR, and ATM are all kinases involved in DNA damage repair and have been of significant recent interest due to the success of PARP inhibitors and the concept of synthetic lethality. We have highlighted a few DNA-PK inhibitors and ATR inhibitors recently. The discovery of [...]

Context. T-690 (Takeda) is an oral GCS inhibitor that is brain-penetrant, non-basic, and non-competitive with UDP-glucose. We recently highlighted a glucosylceramide synthase (GCS, aka CGT) inhibitor in Ph. III (Sanofi’s venglustat ). GCS inhibition may reduce glycosphingolipid levels downstream of its product, glucosylceramide (GlcCer). GCS [...]

Context. MAP855 (Novartis Institutes for BioMedical Research) is an oral MEK1/2 active-site inhibitor. Several MEK inhibitors (e.g. cobimetinib, trametinib) have been approved for cancer, generally derived from the same allosteric pharmacophore. MEK inhibitors continue to be explored in combination with new drug mechanisms, with recent [...]

This article explains what Phase I drug metabolism is, contains a poster summarizing common enzyme-mediated drug metabolism reactions, and provides interesting examples of phase I biotransformations and their impact on drug pharmacology. By Drake Anthony Russell , reviewed by Dr. Dian Su and Dr. Julia Shanu-Wilson. Thanks to Hypha Discovery [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2021, and the results are in. The 2021 choice for Drug Hunter’s Small Molecule of the Year is Pfizer’s CoV-2 M pro Inhibitor, PF-07321332 (nirmatrelvir, Paxlovid) . Published in a November 2021 Science article , the molecule was praised for its [...]

This article reviews the novel drugs approved by the FDA in February 2022. together with Dr. Naveed Yasin, Dr. Vinicius Texeira, and Dr. Jennifer Huen Three novel molecules were approved in February 2022: Small molecules: Pyrukynd (mitapivat) : An oral pyruvate kinase activator approved for the treatment of hemolytic anemia in adults with [...]

This month's edition of Drug Hunter's Molecules of the Month include Principia's reversible covalent BTK inhibitors and a single-dose antimalarial. Thanks to Bryan McKibben, Dennis Koester, Callie Bryan, and Christian Kuttruff for their nominations this month. To access our deep dives into the context, clinical development, mechanisms of action, hit-finding strategies, lead optimization, preclinical pharmacology, and more information and insights you won't find in the papers, subscribe to Premium....

GSK3640254, one of January 2022's Molecules of the Month , is an HIV maturation inhibitor and Ph. IIb clinical candidate (60-180 mg PO QD) with activity against a range of HIV strains with Gag polymorphisms. The first HIV maturation inhibitor to read out clinically was bevirimat (Myriad Genetics), derived from a natural product first [...]

Merck’s oral, macrocyclic PCSK9 inhibitors are among the 12 candidates for 2021's "Molecule of the Year" and have already gotten quite a few votes for 2021’s “Molecule of the Year.” They’ve been called “gamechangers” by readers, with impressive human proof-of-concept. MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily [...]

The FDA recently approved Agios' Pyrukynd (mitapivat, AG-348) , a first-in-class, allosteric activator of pyruvate kinase (PK), for treatment of hemolytic anemia in adults with the genetic condition, pyruvate kinase deficiency. The drug is given orally with a starting dose of 5 mg BID, titrating up to 50 mg BID depending on hemoglobin (Hb) [...]

together with Dr. Jennifer Huen, Saumil Patel, and Dr. Naveed Yasin In 2021, the FDA approved 9 non-radiological novel small molecule drugs for oncology. Excluding melphalan flufenamide, which has already been withdrawn, the remaining FDA-approved novel small molecule oncology drugs of 2021 are: umbralisib (PI3Kδ and CK1ε inhibitor) sotorasib [...]

Contrary to popular belief, pharma is incredibly competitive, with dozens of companies often working on the same hot target at the same time. What sets pharma apart from the outside world though, is how deeply we respect our competitors and other scientists when they succeed at cracking technical challenges. Here, Dr. [...]

In 2021 there were: 50 novel drugs approved by the FDA 27 that CDER considers first-in-class (FIC) 16 first-in-class small molecules (according to CDER) These drugs are the first in their therapeutic class to have a particular mechanism of action [...]

Compound 15 is a gut-restricted inhibitor of NaPi2b, a sodium-dependent phosphate transport protein in the solute carrier (SLC) family. NaPi2b is expressed on the apical side of the small intestine and contributes to absorption of inorganic phosphate in the diet. Chronic kidney disease patients have elevated serum phosphate levels and need [...]

S-217622 is the first oral, non-covalent, non-peptidic SARS-CoV-2 3CL (main protease) inhibitor clinical candidate, currently in Ph. II/III trials as a once-daily oral treatment for COVID-19. Unlike paxlovid , the molecule is a non-covalent inhibitor, which may lead to a better safety profile in large populations, though there is no reason to [...]

asundexian (BAY2433334) is a reversible Factor XIa active site inhibitor previously disclosed at the 2021 EFMC-ISMC conference . This article highlights the Ph. I data of asundexian in healthy volunteers, showing that the drug is well tolerated, with no clinically relevant bleeding-related adverse events or any relevant CYP3A4 modulation. The [...]

MRTX1719 is PRMT5-MTA complex inhibitor for the treatment of MTAP-deleted cancers currently in IND-enabling studies. PRMT5 is a target of active interest with several molecules recently highlighted here . Inhibition of PRMT5 is expected to induce synthetic lethality in MTAP-deleted tumors – however, PRMT5 is also an essential gene for [...]