This article highlights some recent million-dollar molecules, including: Gilead's exclusively licensed preclinical, oral IRAK4 degrader from Nurix Biohaven's exclusively licensed oral, brain-penetrant, dual TYK2/JAK1 inhibitor from Highlightll Pharmaceutical Eli Lilly's acquisition of a Ph. I oral AT 2 R inhibitor from Confo Therapeutics Read [...]

This article discusses scientifically interesting molecules that have unfortunately had negative recent readouts. Aptinyx’s therapeutic approach of targeting positive allosteric modulators (PAMs) of NMDA receptors has hit another setback in Ph. II for NYX-458. The oral, twice-daily MK2 inhibitor from Aclaris Therapeutics has results from its [...]

The AACR 2023 first disclosures presented in the Chemistry in Cancer Research’s “New Drugs on the Horizon” sessions are always fascinating. This article contains the structures of all of the novel small molecule first disclosures presented at AACR in the session, along with notes on their significance, and another molecule disclosed in the [...]

Merck’s oral PCSK9 inhibitor is a surprisingly bioavailable and orally effective macrocyclic peptide with picomolar activity. It recently demonstrated significant LDL cholesterol reduction in Ph. IIb, paving the way for it to enter Ph. III later this year. Roche’s oral, SMN2-directed RNA splicing modifier and first molecule of its kind to be [...]

Pfizer spinout, SpringWorks Therapeutics, was granted priority review by the FDA for its oral gamma secretase inhibitor for the treatment of soft-tissue desmoid tumors, which has no FDA-approved therapies. Meanwhile, Pharming Groups’ oral PI3Kδ inhibitor (licensed from Novartis) received the first and only FDA-approval for the treatment of [...]

Overview. Cyclin-dependent kinase ( CDK2 ) is a target of recent interest , but selectivity has been challenging to obtain. This molecule provides an interesting example of AI being applied to lead generation. Macrocycles can be challenging to design rationally, but can lead to a variety of favorable properties (e.g. in addressing resistance [...]

Induction of fetal hemoglobin expression by a PRC-targeting small molecule. Pociredir (FTX-6058) is an oral, allosteric polycomb repressive complex 2 (PRC2) inhibitor that binds embryonic ectoderm development protein (EED) within this complex, ultimately boosting fetal hemoglobin (HbF) expression . Increasing HbF levels has been shown to [...]

April 1st, 2023 - Molecule of the Day: Curcumin Curcumin is a component of tumeric, and is sold as an herbal supplement, cosmetics ingredient, food flavoring, and food coloring. The molecule is one of the most widely studied therapeutics in history, with papers, reviews, patents, and other sources citing its potential for treating cancer [...]

An old BMS program revitalized as a first-in-class drug in a new indication. Despite Travere Therapeutics having a checkered industry history due to ties to Martin Shrkeli, there appears to be potentially differentiating efficacy for sparsentan’s ( Filspari ) accelerated approval thanks to its novel dual-antagonistic mechanism. It’s also [...]

An oral macrocyclic peptide PCSK9 inhibitor entering Ph. III for hypercholesterolemia later this year, a Ph. I/Ib KRASG12C(ON) tri-complex inhibitor for the treatment of advanced solid tumors, an oral mutant-selective BRAFC600X degrader in Ph. I for BRAF-driven cancers, and an orally available AR-degrading PROTAC in Ph. II for advanced prostate cancers are just some of the examples for this month's MOTM. Learn more about the molecules by navigating to the full reviews on the right (when released) which cover: why the molecules matter, how they were discovered, the key steps behind optimization...

Overview. A common route of resistance to tuberculosis involves Mtb erm37 expression, which expresses an RNA methyltransferase that methylates the A2058 position of the 23S ribosome RNA , hindering macrolide antibiotic binding. The sequanamycins (SEQs) are a class of molecules that overcomes this resistance mechanism, primarily attributed to [...]

The First Disclosures section of the 2023 ACS Spring Meeting in Indianapolis, organized by GSK’s Nikki Goodwin , covers three novel small molecules and an ADC this year. The molecules include: MK-0616, Merck’s macrocyclic oral PCSK9 inhibitor (presented by Abbas Walji ) NX-2127, Nurix’s oral BTK degrader (presented by Jeff Wu ) BI 1015550 [...]

Drug Hunter Reviewer Commentary. With over two decades of experience in neuroscience drug discovery, Drug Hunter reviewer Jake Schwarz says "mGluR2/3 agonists have been explored for schizophrenia, and agonists/PAMS could be tuned to give antagonist/NAM activity, but depression is a new indication. One of the more interesting depression [...]

MC4R antagonism to help gain weight. PF-07258669 is a melanocortin-4 receptor (MC4R) antagonist intended to help increase weight gain, in contrast to MC4R agonists which have been studied extensively in the industry for weight loss (and have notable side effects such as priapism ). The peptidic MC4R agonist, setmelanotide , for example, was [...]

Harnessing a novel mechanism for HIV eradication with a new class of bifunctional molecules. Modern antiretroviral therapies (ARTs) efficiently block HIV-1 replication, but are not completely curative because they can’t deplete viral reservoirs hidden from the immune system within the host genome . PYR01 is an HIV antiviral which, unlike [...]

Preclinical validation for IRAK4 inhibitors for dermatology from activity in human biopsies. Interleukin-1 receptor-associated kinase ( IRAK4 ) is downstream of toll-like receptors (TLRs), which are established mediators of inflammation . Like many immune-signaling nodes (JAK, BTK), this has been of interest for potential treatment of [...]

On Monday, Mar. 27th (12:15 PM ET), our Drug Hunter team will be sponsoring a luncheon at ACS Spring 2023 in Indianapolis with a presentation on scientific gems from 2022’s drug approvals ( request an invitation here ). Each newly approved drug has an interesting scientific story, and you can see our overview of all 36 of the novel small [...]

In 2022, Amgen acquired ChemoCentryx for $4B in cash, primarily for avacopan, a first-in-class treatment approved in 2021 for a rare automimmune condition, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Scientifically, it is notable that avacopan is the first small molecule targeting the complement pathway to be [...]