Spinal Muscular Atrophy (SMA)—the leading genetic cause of childhood mortality—is a disease in which the gene SMN1 is deleted or mutated. The highly similar gene SMN2 can undergo alternative splicing to generate functional protein transcripts of the SMN1 gene product, although native levels of the protein are too low to overcome the pathology [...]

Context. BI-4142 (Boehringer Ingelheim) is a HER2 exon 20 insertion mutant inhibitor being developed for non-small cell lung cancer (NSCLC). Despite the general advances made in HER2-targeted therapy and the existence of several agents targeting HER2-positive breast cancer , a high unmet need exists for patients with HER2 mutant NSCLC [...]

Context. MRTX0902 (Mirati Therapeutics) is an oral brain penetrating SOS1:KRAS protein-protein interaction inhibitor. Since the first report of the druggability of the KRAS G12C mutant, KRAS has been a hotly pursued oncotarget. Notably, the first-in-class sotorasib (Lumakras; Amgen) was recently approved, while Mirati Therapeutics’ highly [...]

Context. “ Compound 33 ” (Merck) is a cGMP-dependent protein kinase G1α (PKG1α) activator cGMP modulation is considered one of the most promising approaches for cardiovascular drug discovery with >30 agents either approved for use or in various stages of clinical development. Although PKGs are the main effector of cGMP, cardiovascular drug [...]

Context. SAGE-718 (Sage Therapeutics) is an oral N -methyl-d-aspartate receptor (NMDAR) Positive Allosteric Modulator (PAM) being developed for cognitive impairment in Huntington’s disease. Aberrant NMDAR signaling has been implicated in several neurological and psychiatric disorders, making the receptor an attractive drug target. Although [...]

Context. RP-6306 is an oral protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1) Inhibitor being developed for various solid tumors. PKMYT1, together with WEE1, make up the WEE family of serine/threonine kinases, which have been implicated in the progression of several cancers, especially solid tumors . At least 4 WEE1 inhibitors [...]

Context. BLU-945 (Blueprint Medicines) is an oral EGFR mutant inhibitor being developed for treatment-resistant non-small-cell lung cancer (NSCLC). Although three generations of EGFR TKIs are available for EGFR -mutant NSCLC, drug resistance and associated disease relapse are still highly prevalent. The widely used third-generation agent [...]

Context. CC-99677 (BMS) is an oral, covalent MAPK–activated protein kinase-2 (MK2) inhibitor being developed for autoimmune diseases. Although p38 is the most heralded member of the p38-MAPK signaling pathway, one that mediates the release of pro-inflammatory cytokines and is implicated in several inflammatory diseases, attempts to directly [...]

Context. CHF-6366 (Chiesi Farmaceutici S.p.A) is a muscarinic antagonist and β2 agonist (MABA) being developed as an inhaled treatment for respiratory diseases. Muscarinic antagonists and β2 agonists both act to inhibit bronchoconstriction, but through different mechanisms, making the combination of both agents a desirable strategy for [...]

Context. “ Compound 3f ” (Janssen) is an oral Factor XIa (FXIa) inhibitor being developed for thromboembolic diseases. The suitability of FXIa as a target in the development of anticoagulation agents stems from observations that the coagulation factor contributes significantly to pathological blood clotting (thrombosis) but plays a negligible [...]

Context. “ Compound 14 ” (Shionogi Pharmaceuticals) is a nicotinamide N -methyltransferase (NNMT) inhibitor. For some “difficult to drug” targets such as protein-protein interactions , peptides are attractive therapeutic modalities due to their high binding specificity and synthetic accessibility. Macrocyclization of peptides may help improve [...]

We're here at ACS Chicago 2022, covering sections of particular interest to drug discovery scientists. Among the highlights are the First Disclosures sections, where companies are sharing structures of clinical candidates for the first time. We'll go more in-depth into the science from the conference soon - for now, here's a high-level [...]

How a Follow-on Drug Can Create Value After a First-in-Class Drug Novel drugs can make a big impact in two main ways—by being first-in-class (FIC) or by being best-in-class (BIC). A novel drug that produces its therapeutic effect by interacting with a new target or that is used to treat a new condition is considered first-in-class (FIC) [...]

This article is Part 5 of a review series covering all the initial public offerings for the biotech and pharmaceutical industries in 2021. Part 1 and Part 2 provided an overview of 2021 IPOs by therapy area, technology, and therapeutic class. Part 3 and Part 4 provided a deep dive into the 2021 IPOs for oncology-focused companies developing [...]

As biotech experts, risk taking is part of our business model. Without scientific and business risk, inventions would not occur and businesses would not grow. How do we know we are taking appropriate risks at the right time? How do we know we are using agile drug development strategies by tracking, understanding, and mitigating risk as our [...]

In this guest article, Dr. Luíza Cruz breaks down the synthesis of Gilead’s lenacapavir (GS-6207), Drug Hunter’s Small Molecule of the Year – 2020 . Lenacapavir is a promising first-in-class, long-acting injectable (LAI) HIV capsid inhibitor . Interesting synthetic steps employed in this route include an unusual sodium chlorite-mediated [...]

Readers have been asking for more molecules, so we started a new feature that highlights a few of the molecules we liked that didn’t make it into Molecules of the Month. There were six runners-up this month, including an orally available ALK2 inhibitor and a direct AMPK activator for X-linked adrenoleukodystrophy. You can read more about all [...]

A covalent KRASG12R inhibitor used as a proof-of-concept for covalent arginine modification, an oral dihydroorotate dehydrogenase inhibitor being developed for acute myelogenous leukemia, and a first-in-class YAP-TEAD protein-protein are some examples of this month's MOTM. In the slide deck, you'll find a compound that has over 1400-fold selectivity for Cathepsin K over other biologically relevant cathepsins and a hydroxylated compound that is more than 1900x more selective than its non-hydroxylated counterpart. Check out all ten minireviews in the slide deck, which covers: Where are the Mole...