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 [...]

PI3 kinases are part of the PI3K/Akt/mTOR signaling pathway that is downstream of Receptor Tyrosine Kinases (RTKs), G-protein-coupled receptors (GPCR), and GTPases such as KRAS. Since their identification in the 1980s, and due to their central role in cancer, the therapeutic targeting of the phosphatidylinositol-3-kinase (PI3K), and more [...]

There have been numerous reviews on the impact of AI/ML in drug discovery looking at broad numbers, but with the volume of companies in the space, few have spelled out exactly what these companies are working on to paint a picture of what the landscape of AI/ML in small molecule drug discovery actually looks like today. We concluded part II [...]

Despite significant investment over the past decade, only a handful of companies are now bringing clinical candidates discovered with the assistance of AI/ML forward. Though there’s a looseness to what should count as an “AI-discovered drug,” here we highlight internally-generated drug programs from companies focused on leveraging AI/ML in [...]

In a recent webinar , we surveyed our audience and were surprised to see that a significant majority of attendees thought the application of artificial intelligence and machine learning (AI/ML) methods was the most exciting area for drug discovery, beyond even degraders or molecular glues. Machine learning methods have been increasingly [...]

At AAPS 2022, I hosted a symposium where Ovoca Bio plc's Head of Research, Mikhail Lomonosov told us about orenetide. Orenetide is an internationally approved peptide drug for hypoactive sexual desire disorder (HSDD) (think Viagra for women). It appears to work within a few weeks in humans with a solid safety profile - Mikhail noted that one [...]

Drug candidates exhibiting atropisomerism are often considered challenging for development by pharmaceutical professionals from synthetic and regulatory perspectives. Molecules that exist as stable atropisomers can be acceptable for development, but are often difficult to synthesize in their isomerically pure form. Modern catalysis [...]

After evaluating thousands of articles and hundreds of candidates, a brain-penetrant pre-mRNA splicing modulator, a gut-restricted candidate for Parkinson’s disease (you read that correctly), and a male contraceptive mechanism are among this highlights of this edition of Molecules of the Month.  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 wee...

Context. Upacicalcet (Sanwa Kagaku Kenkyusho Co) is a calcium-sensing receptor (CaSR) agonist being developed for secondary hyperparathyroidism (SHPT). The IV drug, first identified in "kokumi-flavor" studies of γ-glutamyl peptides, was approved for SHPT in Japan in 2021 and is currently being developed for the US and other markets [...]

Context. AZD1390 (recently published on by University of Minnesota) is a brain-penetrating Ataxia-Telangiectasia Mutated (ATM) kinase inhibitor under development for brain tumors. The kinase, known for its critical role in the repair of lethal DNA lesions induced by radiotherapy treatment, is considered an attractive target for CNS tumors [...]

Context. “Compound 39 ” (RAPT Therapeutics) is a general control nonderepressible 2 (GCN2) protein kinase inhibitor. As the master regulator of the integrated stress response triggered by cellular stress in the tumor microenvironment, GCN2 has been implicated in tumor progression and immune escape, making the kinase an attractive oncotarget [...]

Context. Neflamapimod (EIP Pharma, VX-745 ) is an oral, brain-penetrant p38α kinase inhibitor under development for neurodegenerative disorders. Among the roles of p38α MAPK is the activation of Rab5 , a small endosome-associated Ras GTPase that regulates intracellular trafficking pathways . This, coupled with the involvement of Rab5 in the [...]

Context. ICeD-2 (Merck) is a dipeptidyl peptidase 9 (DPP9) inhibitor under development for HIV-1 infections. Despite the significant advancements in antiretroviral therapy research leading to the approval of some highly effective treatments , the cure for HIV-1 infection has been elusive. A phenotypic screen looking at compound-induced HIV-1 [...]

Context. Ziftomenib (KO-539; UMich) is an oral menin inhibitor being developed for mixed-lineage leukemia 1 (MLL1)-rearranged or NPM1 -mutated acute myeloid leukemia (AML). Although a tumor suppressor in endocrine glands, the scaffold protein menin is an essential cofactor for leukemogenesis in leukemia subsets driven by the rearrangement of [...]

Context. GB1211 (Galecto Biotech) is an oral galectin-3 inhibitor under development for fibrotic disease. First described in 1971, galectin-3 , a unique subtype of a 15-member family of carbohydrate-binding proteins, has been implicated in a host of different diseases, such as cancer, liver cirrhosis, and atherosclerosis. Incredibly, over [...]

Context. GST-HG131 (WuXi AppTec) is an oral hepatitis B virus (HBV) inhibitor which lowers hepatitis B antigen (HBsAg) levels which entered clinical development in Chinese subjects for chronic hepatitis B infection. Despite the significant research strides made in the elucidation of the biology of HBV, chronic HBV infection continues to [...]

Context. CH7057288 (Chugai Pharmaceutical Co) is an oral pan-tropomyosin receptor kinase (TRK) inhibitor. Chromosomal rearrangements in the NTRK1–3 genes that encode gene fusions leading to TRK fusion proteins have been shown to drive oncogenesis in many human tumors. Several inhibitors targeting kinase fusions have been developed and are [...]