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...

Context. Iclepertin (BI 425809; Boehringer Ingelheim) is an oral glycine transporter-1 (GlyT1) inhibitor being developed for cognitive impairment associated with schizophrenia (CIAS) . The ineffectiveness of currently available antipsychotic medications in improving negative symptoms and cognitive deficits leaves a significant unmet need for [...]

Context. DNL201 (Denali Therapeutics) is an oral, CNS-penetrating, ATP-competitive leucine-rich repeat kinase 2 (LRRK2) inhibitor being developed for Parkinson’s disease (PD) . PD remains incurable; current treatment options only alleviate disease symptoms and do not prevent progression. Due to its well known involvement in familial and even [...]

Context. BMS-986120 is an oral protease-activated receptor 4 (PAR4) inhibitor that was being developed for arterial thrombosis . PAR4 was long considered a redundant “backup” receptor to the more popular and well-researched PAR1 receptor, owing in part to the higher thrombin levels required for activation and the slower signaling response the [...]

Context. EZM0414 (Epizyme, Inc.) is an oral SETD2 inhibitor being developed for hematological malignancies . Although several genetic studies have proposed that the histone methyltransferase SETD2 is a tumor suppressor in solid cancers, inhibition of the enzyme may be desirable in some hematological malignancies such as leukemia and lymphoma. [...]

Context. “Compound 23” (LEO Pharma) is an oral IL-17A protein−protein interaction modulator being developed for psoriasis and other inflammatory diseases . Like most cytokines, the involvement of IL-17A in chronic inflammatory diseases has been well-researched . IL-17A is the key cytokine that mediates psoriasis , and targeting it or its [...]

Context. BMS-986339 (BMS) is an oral farnesoid X receptor (FXR) agonist being developed for nonalcoholic steatohepatitis (NASH) . Considered the master regulator of bile acid homeostasis, the nuclear receptor FXR may be an attractive target for diseases such as NASH, where bile acid dysregulation has been implicated. Currently, the only [...]

Context. MK-0159 (Mitobridge) is an oral CD38 inhibitor being developed for cardiovascular diseases. D ue to its NADP + depleting activity, which has implications for calcium homeostasis, the cell surface marker CD38 has attracted attention as a suitable target for developing cardiovascular disease agents. Although two monoclonal antibodies [...]

Context. TAS1553 (Taiho Pharmaceutical) is an oral ribonucleotide reductase (RNR) inhibitor with antitumor activity . As the enzyme that catalyzes the rate-limiting step for deoxyribonucleotide triphosphate (dNTP) synthesis in cells, RNR has long been of interest to anticancer drug discovery efforts, especially since unlimited dNTP supply is [...]

Context. NTQ1062 (Nanjing Chia-Tai Tianqing; CTTQ) is an oral ATP-competitive Akt inhibitor being developed for cancer . Because the PI3K/Akt/mTOR pathway is one of the most commonly disrupted pathways in cancer, inhibitors targeting one or more of the three kinases have been hotly pursued. To date, five PI3K and three mTOR inhibitors have [...]

Context. Apararenone (Mitsubishi Tanabe) is an oral nonsteroidal mineralocorticoid receptor (MR) antagonist . Agents with the ability to modulate the nuclear receptor MR have been pursued for at least 80 years. Spironolactone , the first-in-class MR (steroidal) antagonist, was approved in 1960, with the more selective eplerenone (also [...]