The real magic happens when chemists can integrate computational models into their assay cascades, thanks to trust in their predictions. To get there, grounding computational predictions in physics and experimental reality makes all the difference. In this article, Abba E. Leffler, Ph.D. from Schrödinger tells us about: How to make [...]

Ten of the most interesting and instructive small molecule case studies that appeared in the literature in Oct. 2022 are shown below. Learn more about the molecules by navigating to the full reviews on the right which cover: why the molecules matter, how they were discovered, the key steps behind optimization, how the drugs work, why the targets were chosen, interesting toxicology and clinical data, and more. Sign up for our free weekly newsletter to get more content like this straight to your inbox. Not a member? Get a free trial to check out substructure search and more features....

In August 2022, olipudase alfa (Xenpozyme), a hydrolytic lysosomal sphingomyelin-specific enzyme indicated for non–CNS manifestations of acid sphingomyelinase deficiency (ASMD), was approved in the US and Europe. This Premium deep dive into Xenpozyme includes: the industry context, the clinical data, the target rationale, the mechanism of [...]

Context. ACT-660602 (Idorsia Pharmaceuticals) is an oral chemokine receptor CXCR3 antagonist being developed for autoimmune diseases. Chemokines and their receptors make up the signaling system that is responsible for immune cell migration. This is important for the innate immune system’s ability for fighting infection, but dysregulation of [...]

Context. “Compound 23” (Merck) is a selective oral cathepsin K (CatK) inhibitor intended for osteoarthritis. Osteoarthritis affects around 15% of the population, and current treatments offer only symptom relief, highlighting the need for targeted treatments. Prior to the “compound 23”, several CatK inhibitors had reached clinical [...]

Context. “ Compound 7 ” (NIBR) is an oral Trypanosoma brucei 20S proteasome inhibitor being developed for Human African Trypanosomiasis (HAT). African sleeping sickness , or HAT, is caused by a parasite in the genus Trypanosoma .  The parasite is spread by the Tsetse fly, and the lifecycle of the parasite involves a phase in the blood of the [...]

Context. GNE-064 (Genentech) is an oral inhibitor of the bromodomains of SMARCA2/4 and PBRM1 being developed as a tool compound. Many proteins contain bromodomains (there are 61 in the human genome), which recognize acetyl lysines and are involved in regulating gene transcription. Proteins that contain bromodomains are often mutated in [...]

Context. “ Compound 6 ” (Novartis) is a first-in-class YAP-TEAD protein-protein inhibitor. The TEAD transcription factor and its coactivator YAP and WWTR1/TAZ of the Hippo pathway are responsible for directly regulating the expression of genes involved in cell proliferation and organ size. Several kinases in the cascade have recently gained [...]

Context. Obicetrapib (Monash University and NewAmsterdam Pharma) is an oral selective cholesteryl ester transfer protein (CETP) inhibitor being developed for dyslipidemia. Patients with high cardiovascular risk typically aim to lower cholesterol with a combination of statins, diet, and exercise, but this is often not enough . A foundational [...]

Context. SPH3127 (Mitsubishi Tanabe and Shanghai Pharmaceuticals) is an oral direct renin inhibitor (DRI) being developed for hypertension. The renin-angiotensin-aldosterone system is responsible for regulating blood pressure. Existing drugs treat hypertension by targeting angiotensin-converting enzyme (ACE) and the angiotensin II receptor [...]

“Compound 3” (UCSF) is a covalent KRAS G12R inhibitor used as a proof-of-concept for covalent arginine modification. KRAS is the first oncoprotein to be identified and is a well-known cancer-driving protein. As one of the most frequently mutated proteins in pancreatic and colorectal cancers, residues that are frequently mutated are [...]

Context. AZD4831 (AstraZeneca) is an oral covalent myeloperoxidase (MPO) inhibitor being developed for heart failure. Almost half of chronic heart disease patients suffer from heart failure with a preserved ejection fraction (HFpEF) and have an estimated five-year mortality rate of 75% . Improvement in vascular structure could help these [...]

Context. “ Compound 19 ” (Janssen) is an oral dihydroorotate dehydrogenase (DHODH) inhibitor being developed for acute myelogenous leukemia (AML). DHODH is a ubiquitously expressed, essential enzyme in the de novo pyrimidine biosynthesis pathway. Despite its ubiquitous expression and lack of known mutations or overexpression in cancer, DHODH [...]

In August 2022, the European Medicines Agency granted Marketing Authorization to lenacapavir (Sunlenca), the first-in-class bi-annually dosed HIV capsid inhibitor indicated for multidrug-resistant HIV-1 infection. This Premium deep dive into Sunlenca includes: the industry context the clinical data the target rationale the mechanism of action [...]

We did a deep dive into the pharmaceutical industry’s 2022Q2/Q3 news, and there’s a ton of exciting updates to share. In this review, we highlight some emerging companies, technologies, and drug discovery modalities we thought drug hunters would find interesting, including: New strategies for covalent protein modification Different methods [...]

Our team conducted a review of all  the biotech acquisitions of 2021 and distilled it down to the acquisitions of drug discovery-focused biotechs. Navigate the 2021 M&A Series the top overall drug discovery M&A transactions by value (Part 1) the transactions with disclosed upfront payments (Part 2) the most valuable small molecule [...]

Amgen has acquired ChemoCentryx in a deal that includes lead molecule avacopan (Tavneos), a first-in-class orally bioavailable small molecule complement 5a receptor (C5aR) antagonist approved as an adjunctive treatment to standard of care therapy for adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated [...]

You’ve read about the top 10 molecules with publications from July, but what about the ones we found interesting that didn’t make it into Molecules of the Month? There were six runners-up this month, including a selective covalent K-Ras(G12S) inhibitor with a butyrolactone warhead, a κ opioid receptor agonist, and a dinucleotide STING agonist [...]