Overcoming FGFR mutation resistance and FGFR1-mediated hyperphosphatemia toxicity through isoform-selective FGFR2/3 inhibition. “Compound 29” is an ATP-competitive fibroblast growth factor receptor (FGFR) 2/3 inhibitor with subnanomolar potency. FGFR is a receptor tyrosine kinase (RTK) involved in cell differentiation, proliferation [...]

Toward CTPS1 inhibitors as a safer alternative to nucleoside chemotherapeutics: Rapidly growing cancer cells are critically dependent on synthesis of nucleotides, the building blocks of RNA and DNA. Blocking the synthesis of nucleotides is a tried-and-true mechanism of action for widely used chemotherapeutics such as cytarabine (ara-C) and [...]

WASp as a new target for hematological cancers. Wiskott-Aldrich syndrome protein ( WASp ) is a protein almost exclusively expressed in hematopoetic cells that promotes actin polymerization. The WAS gene plays an important but not fully understood role in human immune cell biology, illustrated by WASp deletion in B-cells inducing autoimmunity [...]

Revisiting AMPK activation with β2-AMPK isoform potency. “ Compound 14d ” (Shionogi & Co.) is a highly potent, dose-dependent adenosine monophosphate activated protein kinase (AMPK) activator being investigated for its blood-glucose-lowering effects. AMPK became a target-of-interest for the treatment of diabetes due to its role in regulating [...]

Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs , their bulkier bivalent counterparts, to the [...]

Today, ozanimod is a likely megablockbuster drug approved for ulcerative colitis and multiple sclerosis. But before it became the first S1P modulator approved in ulcerative colitis, it received a scary, headline-making “ Refuse to File ” letter from the FDA due to insufficient preclinical characterization of an active metabolite RP112273 [...]

A potential first-in-class drug for NASH, a mutant-selective degrader of PI3Ka, and a bi-steric inhibitor of mTOR are some examples of this month's MOTM. 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 here to get more content like this straight to your inbox. Not a member? Get a free trial to check out substructure search and m...

Context. AN15368 (Anacor Pharmaceuticals) is an oral Cleavage And Polyadenylation Specificity Factor (CPSF3) inhibitor being developed for Chagas disease, also known as American trypanosomiasis. Chagas disease is caused by Trypanosoma cruzi and is estimated to affect 6-7 million people worldwide, primarily those living in Latin America. The [...]

Context. Sebetralstat (KalVista Pharmaceuticals) is an oral, on-demand plasma kallikrein (PKa) inhibitor intended for hereditary angioedema (HAE). As an on-demand medication, it can be administered to treat acute attacks rather than chronically to prevent attacks. Its structure was first disclosed at the ACS Spring Meeting earlier this year [...]

Context. “ Compound 57 ” (Roche) is an oral allosteric EGFR L858R inhibitor being developed for NSCLC. Drug resistance and associated disease relapse continue to remain unmet needs for patients with NSCLC tumors harboring EGFR mutations, despite the availability of three generations of TKIs for EGFR+ NSCLC. Although the widely used [...]

Context. BI-0474 (Boehringer Ingelheim) is a covalent KRAS G12C inhibitor. KRAS continues to be a hotly pursued oncotarget since the first report by the Shokat group of the druggability of the KRAS G12C mutant. Recently, Amgen’s first-in-class sotorasib (Lumakras) was approved, while Mirati Therapeutics’ adagrasib (MRTX84) may be approved in [...]

GDC-2394 (Genentech) is an oral NLRP3 inflammasome inhibitor. The NLRP3 inflammasome is the best studied and most characterized inflammasome , with the protein playing a key role in the detection of inflammatory danger signals which are a hallmark of many inflammatory diseases. Hyperactivation of the NLRP3 has been implicated in the [...]

Context. “ Compound 5g ” (Incyte) is a selective cyclin-dependent kinase 2 (CDK2) inhibitor. Although CDK2 is a highly pursued cancer drug target , inhibitors targeting the key cell cycle regulator have not enjoyed similar success as CDK4/6 inhibitors , in part due to the major challenge of mitigating off-target CDK1/9 activity through the [...]

Context. AZD1656 (AstraZeneca)is an oral glucokinase (GK) activator (GKA) for hyperglycemia in type 2 diabetes mellitus. Despite GK being first reported more than 50 years ago and subsequent extensive research efforts , a GKA is yet to be approved. Most GKAs have failed in clinical development owing to an increased risk of hypoglycemia and [...]

Context. JNJ-64264681 (Janssen) is a covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed for hematological malignancies. The first-in-class irreversible BTKi ( ibrutinib ) was approved in 2013, while many others have been approved or are in clinical development with potentially reduced off-target effects . We recently covered [...]

Context. UCB7362 (UCB Biopharma) is an oral plasmepsin X (PMX) inhibitor being developed as an antimalarial agent. Malaria is a protozoan disease caused by Plasmodium sp. and remains a significant public health concern in many parts of the world, with 627,000 reported global deaths in 2020 despite the significant strides in the antimalarial [...]

Context. BAY-069 (Bayer) is a branched-chain amino acid transaminase (BCAT) 1/2 inhibitor. Involved in the synthesis and breakdown of branched-chain amino acids, BCAT1 and BCAT2 have also been implicated in several diseases, including various cancer types, with the ligandability evidenced by the many reported inhibitors . Tool compound [...]

Drug lipophilicity is a core property that contributes to drug solubility, permeability, metabolic disposition, and other key properties. Increasing lipophilicity can often lead to increased affinity in relevant biological assays due to the hydrophobic nature of many protein binding pockets,  but this may also increase promiscuity to [...]