Context. ”Compound 53” (University of Texas Southwestern Medical Center) is a stimulator of interferon (IFN) genes (STING) agonist . STING agonists have been heavily pursued in cancer immunology as increasing data suggests that the efficacy of immunotherapy can be enhanced by proteins such as STING that can induce a strong innate immune [...]

Context. JDQ443 (Novartis Institute for Biomedical Research) is an oral KRAS^G12C inhibitor being developed for various advanced solid tumors . Despite accounting for 85% of RAS oncogenic mutations in all cancers, KRAS was considered undruggable until 2013 when a report describing the targetability of the KRAS^G12C mutant by small molecule [...]

Context. DS69910557 (Daiichi Sankyo) is an oral inhibitor of parathyroid hormone (PTH) type 1 receptor (PTHR1) being developed as a calcium-lowering drug. The well-characterized secretin class receptor PTH1R is a principal regulator of bone remodeling and calcium ion homeostasis which makes it an attractive target for some endocrinopathies [...]

Context. AZD4625 (AstraZeneca) is an oral inhibitor of KRAS G12C being developed for the treatment of advanced solid malignancies . As indicated for JDQ443, the KRAS G12C mutation presents the perfect “Achilles heel” for targeting a KRAS protein previously thought undruggable. The protein is a current hot topic in precision oncology , with [...]

Context. “ Compound 41” (Vanderbilt University School of Medicine) is an oral WD40 Repeat Domain 5 (WDR5) inhibitor being developed for various human cancers . The well-established role of epigenetic abnormalities in cancer development and progression has led to extensive studies to identify various epigenetic cancer inhibitors. Currently [...]

JBJ-09-063 (Dana-Farber Cancer Institute) is an oral allosteric EGFR inhibitor currently in pre-clinical development for the treatment of EGFR L858R -mutant non-small cell lung cancer (NSCLC) . Despite the availability of 3 generations of EGFR TKIs for the treatment of EGFR-mutant NSCLC, drug resistance and associated disease [...]

Context. ABBV-318 (AbbVie) is a CNS-penetrating, oral inhibitor of Na v 1.7/Na v 1.8 being developed for pain treatment . Despite being a highly validated pain target due to its important role in excitable cells, Na v 1.7 inhibition has not lived up to its potential, and translation of the promising preclinical observations to human studies [...]

Context. Tenapanor (Ardelyx) is an oral, first-in-class Na + /H + exchanger isoform 3 (NHE3) inhibitor approved by the FDA for irritable bowel syndrome with constipation (IBS-C) in adults. NHE3 is expressed predominantly in the gut and kidney and its role as a key mediator of sodium and water homeostasis makes the protein an ideal target for [...]

Context. Lenrispodun (Intra-Cellular Therapies) is a phosphodiesterase (PDE) type 1 (PDE1) inhibitor being developed for CNS and non-CNS disorders, including heart failure, and cancer. Studies to identify PDE inhibitors date back at least 30 years, and at least 10 drugs have been approved targeting other PDE proteins (spearheaded by the PDE5 [...]

In this highlight, Dr. Dennis C. Koester reviews treatment options for HIV and explains how small molecule long-acting injectables (LAIs) are offering significant promise in both HIV treatment and prophylaxis. A Coming Paradigm Shift for HIV Treatment and Prophylaxis By Dennis C. Koester The surge of the coronavirus pandemic has made our [...]

We did a comprehensive review of industry news in 2022Q1 (there was.. a lot of stuff to cover). In this article, we highlight some emerging companies, technologies, and drug discovery modalities we thought drug hunters would find interesting, including: New platform companies focused on drug discovery Different approaches to glues and [...]

In this minireview, Dr. Romyr Dominique introduces three key concepts in fragment-based drug discovery and shares his favorite articles and resources on fragment-based drug discovery. Fragment-based drug discovery has emerged as a key tool for acquiring starting points for challenging targets like KRAS. By Dr. Romyr Dominique What is FBDD, or [...]

The gem-dimethylcyclopropyl group is a key element in drugs, candidates, and agrochemicals, with a recent example being nirmatrelvir, the active ingredient in the Pfizer COVID-19 drug, Paxlovid. Here, we review synthetic strategies used to produce the key gem-dimethylcyclopropylproline intermediate, which may now be required in hundred-ton [...]

We did a comprehensive review of industry news in 2022Q1 (there was.. a lot of stuff to cover). This article highlights companies focused on drug discovery that IPO’d in the first quarter. The Drug Discovery IPO Market Slowdown As everyone knows, biotech’s been in a bear market since Feb. 2021 (with the entire $XBI index down more than 50% [...]

In this minireview, Drs. Jayme L. Dahlin and Michael A. Walters summarize the different mechanisms by which molecules can be AICs (assay interference compounds), a subset of which can be flagged as PAINS (pan-assay interference compounds) by a popular set of substructure filters. They bin these into non-technology-related interference [...]

The FDA approved five new drugs in 2021 for use for genetic conditions, including molybdenum cofactor deficiency, Von Hippel-Lindau (VHL) disease, achondroplasia, and progressive familial intrahepatic cholestasis (PFIC). This article and slide deck reviews each in detail, including their mechanisms of action, originators, key clinical data [...]

There were two novel small molecules approved in April 2022: mavacamten (Camzyos), an oral cardiac myosin inhibitor oteseconazole (Vivjoy), an oral antifungal ( jump to section ) This deep dive explores each drug in more detail, including the industry context, the clinical data, the target rationale, mechanisms of action, and drug origins [...]

Recently, Dr. Alf Claesson (CEO of Awametox AB, inventor of SpotRM, and previously Principal Scientist and Section Head at AstraZeneca/Astra AB, Sweden) reached out about our resource on the bioactivation of structural alerts . Dr. Claesson shared the helpful notes that: carboxylic acids forming thioesters with CoA might be a greater danger [...]