While KRAS(G12C) has been the most readily targeted form of KRAS thanks to its reactive cysteine residue, other mutations such as KRAS(G12D) make up the majority of KRAS-mutated cancers. In this roundup, we highlight 12 inhibitors, degraders, and other molecules that reflect progress in overcoming this challenge, including some of the first clinical candidates targeting non-KRAS(G12C)-mutant tumors, and why these molecules are notable.

December 2023 was a big month for estrogen receptor (ER) degraders featuring stories from Phase III candidates vepdegestrant, camizestrant, and OP-1250 (not included here) to treat breast cancer. Unfortunately, Phase II trials of Boehringer Ingelheim’s selective ENaC inhibitor, BI 1265162, to treat CF and Phase III trials of Serono’s much anticipated BTK inhibitor, evobrutinib, to treat MS were both terminated. Additionally, preclinical candidates from Genentech and Roche, promising Phase II candidates to treat myelodysplastic syndrome and atrial fibrillation, and a Phase III candidate to trea...

While gadolinium-based MRI contrast agents (GBCAs) are important for enhancing MRI and MRA imaging, several studies have shown that gadolinium can be retained in the brain and body for months to years after GBCA injection, prompting the FDA to issue box warnings to the drug class. Gadopiclenol, the ninth approved GBCA, was designed to enable use of a lower gadolinium dose than other agents. This highlight reviews how it works and why it’s notable.

There were several key clinical readouts in Dec. 2023 for small molecules in areas ranging from non-opioid pain management to sickle cell disease. While most results were positive, one pivotal trial led to a program discontinuation. This roundup highlights key data recently reported for selected molecules targeting NaV1.8, BTK, and more.

The 34 small molecule drug approvals of 2023 are summarized in this poster and article with the structures, mechanisms of action, originators (& marketers), indications, and links to deep-dive reviews and more information about each drug.

Last December, the pharmaceutical industry witnessed many important updates for clinical molecules, ranging from neurology-based therapies to anti-tumors and radiopharmaceuticals, in addition to the unfortunate discontinuations. In case you missed it, here is a recap of the most notable news updates in the pharma world for December 2023

2023 was an incredible year in drug discovery. Drug Hunter featured many remarkable case studies last year including campaigns on challenging targets like KRAS, programs employing emerging modalities like degraders or oral macrocyclic peptides, and compounds with fascinating properties like allostery and mutant-selectivity. In case you missed these stories, here are the top 12 most popular Drug Hunter case studies published in 2023.

Drug Hunter regularly reviews trends and topics of industry interest, from hot new molecules from conferences to recently notable targets and technologies. Here are ten of the most popular reviews accessed on Drug Hunter in 2023.

The educational and professional resources on Drug Hunter are meant to help you with your job on a regular basis. Here are the ten most popular resource pages on Drug Hunter in 2023 - if you haven’t found and used these already, check them out!

AM-2-19 (SF001) is an analog of the notoriously toxic IV antifungal drug, amphotericin B (AmB). Compared with AmB, AM-2-19 is significantly less toxic against primary human cells and in mice, while more broadly active against fungal pathogens including antifungal drug-resistant strains. SF001 received Fast-Track Designation from the FDA in 2023 and has progressed to Ph. I clinical development. This article highlights the history of antifungal polyene natural products, a new mechanistic hypothesis for polyene antibiotic activity, and the design of 3rd generation Erg-specific polyenes.

An aldosterone synthase inhibitor, a pFOX inhibitor, a brain-penetrant MEK1/2 inhibitor, and several other modulators had major trial results disclosed recently. In case you missed them, this article rounds up key results of general industry interest, with representative patent structures for undisclosed molecules. Read this review to get a sneak peek at potential future approvals, as well as some informative disappointments.

Last November saw several notable updates for molecules we previously covered on Drug Hunter. These updates ranged from positive Ph. III results and NDA submission to failed clinical trials and discontinuation, for TTR, FXIa, GLP-1R modulators, and more. In case you missed it, this article is a round-up of these clinical updates from Nov. ’23.

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here we have compiled a table of >70 additional molecules that were of interest in November 2023 along with some highlights from some of our favorites below.

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

Leniolisib is a selective PI3Kδ inhibitor that received approval in March 2023 from the FDA as a first-in-class treatment for activated PI3K-δ syndrome (APDS), a genetic immunodeficiency disorder caused by PI3Kδ activation. The leniolisib discovery program is notable for several reasons: it is a first approval for a PI3K inhibitor outside of oncology; the first approved drug for APDS; has a novel chemotype that appears to avoid safety issues that led to black box warnings seen with other PI3K molecules; and it overcame a polymorph issue with an early lead that led to inconsistent exposures.

This month features some remarkable molecules including an allosteric pan-mutant isoform-selective PI3Kα inhibitor, a potentially best-in-class CNS-penetrant PARP1 inhibitor and trapper, and a photoswitchable HCN blocker to treat pigmentosa and choroideremia. Additionally, the IRAK4 degrader, KT-474, makes the top of the list this month with positive results from the molecule’s Ph. I trials for AD and HS. You can read Drug Hunter’s full case study on KT-474 here and stay tuned for more detailed case studies on these fascinating molecules. In the meantime, you can check out the recent articles...

Several multi-million dollar acquisitions or license agreements took place in November 2023 for hot drug targets, with assets from selective PARP1 inhibitors to GLP1R agonists, and others. This recent news roundup highlights the notable acquisitions by pharma companies for rights to molecules in a range of different indications, with illustrative patent examples for undisclosed structures.

JNJ-54175446 is an oral, CNS-penetrant P2X7 ion channel antagonist targeting a novel pathway linking neuroinflammation and depression, with recently published Ph. I data in major depressive disorder (NCT02902601, initiated in 2016). The Janssen program is notable as a pioneering early example of a neuroinflammation program started at a time before NLRP3 or neuroimmunology were commonly discussed topics, as they are today [...]