Molecule Highlights
In this roundup, we present a curated selection of over 50 molecules from October that captured our team’s interest. We highlight our top picks and offer insights into what makes them stand out.
Morphic Therapeutic’s MORF-627 is an oral αvβ6 integrin inhibitor designed to treat IPF by blocking the TGFβ pathway. The Morphic team leveraged SBDD and FEP+ during lead optimization to enhance permeability and isoform selectivity. This article highlights the team’s focus on inhibiting the “bent-closed” conformation of αvβ6 as well as the linker design that led to the “chameloenicity” of the lead compound. The impressive multispecies PK and in vivo efficacy of MORF-627 in preclinical models was unfortunately accompanied by oncogenic toxicity that prevented it from reaching clinical trials.
Revumenib (Revuforj®) is approved by the FDA as an oral, first-in-class menin-MLL interaction inhibitor for acute leukemia (AL). Since inhibition of the menin-MLL fusion protein interaction is selective for AL with a KMT2A translocation, it does not compromise normal hematopoietic function. This article covers the background, optimization and clinical development that has led to the approval of this groundbreaking new drug in a hard-to-treat indication.
Check out our searchable, annotated database featuring our curated selection of the most important drug discovery patents published in October 2024.
Medicinal chemists often face cardiotoxicity issues linked to inhibition of the hERG (human ether-à-go-go-related gene) channel. In a recent Coffee Chat, Drug Hunter CEO Dennis Hu, Director for Industry Research and Relations Dennis Koester, and Senior Scientific Editor Matt Hesse discussed ways to reduce hERG risks during lead optimization. They described approaches to reduce hERG affinity while retaining on-target potency and discussed case studies of drug programs that used these strategies to eliminate their hERG issues.
The 2024 edition of MCR (Medicinal Chemistry Reviews), edited by Joachim Rudolph and Will Watkins, has just been published by the American Chemical Society MEDI Division. Featuring contributions from a global team of section editors and authors, MCR offers concise updates on a broad range of contemporary drug discovery topics, making it an invaluable resource for both aspiring and experienced medicinal chemists.
Nurix’s NX-2127 is an orally bioavailable BTK degrader that exhibits in vivo degradation across species and has advanced into first-in-human clinical trials for relapsed/refractory B-cell malignancies. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Nurix's NX-2127 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.
Understanding how a small molecule ligand binds to its target is valuable in drug discovery, because it enables more efficient optimization through structure-based design, better mechanistic understanding of molecular pharmacology, and greater confidence in the therapeutic hypothesis from both safety and efficacy perspectives. Recently, Drug Hunter highlighted methods for target identification when the target is unknown.
Chiesi Farmaceutici’s CHF-6523 is an inhaled, lung-restricted, selective PI3Kδ inhibitor designed to provide relief to patients with COPD. Its development involved optimization of permeability and solubility as well as identification of a solid form amenable for dry powder inhalation. Disclosed at the EFMC-ISMC 2024 joint conference in Rome, Italy, this article covers the structure, development, and early clinical data of CHF-6523, which ultimately indicates that PI3Kδ inhibition may not provide clinical effect in reduction of lung inflammation.
AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AZ’s clinical candidate, AZ3470. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots.
BAY 2413555 is a M2R PAM that has the potential to counter parasympathetic withdrawal and restore autonomic balance in heart failure patients. The preclinical and clinical data of BAY 2413555 showed it has positive effects on heart rate and heart rate variability and a relatively long human t1/2 of 37 h. The Ph. I trial, however, was terminated in March 2024 due to findings from a chronic toxicology study. This article covers the discovery of BAY 2413555, presented by Alexandros Vakalopoulos of Bayer at the EFMC-ISMC 2024 conference in Rome and published in the Journal of Medicinal Chemistry.
October’s Molecules of the Month include a small molecule that leverages induced proximity to activate mutant p53, along with Roche’s highly potent and selective MAGL inhibitor for CNS disorders. We also highlight two inhibitors of αvβ6, a key target for fibrotic diseases but linked to notable safety risks. Other featured molecules include an oral therapy for PKU with newly published Ph. III data [...]
This October roundup features key clinical updates, including FDA approvals, significant trial results for major drug candidates, the initiation of new clinical trials, and updates on halted studies.
CDI (Clostridioides difficile) infection is a leading cause of healthcare-associated diarrhea with significant morbidity and mortality, and with the rise of hypervirulent and resistant strains, novel and selective antibiotics to treat these infections are needed. Cadazolid, a hybrid antibiotic that combines pharmacophores of two classes of antibacterials, demonstrated potent activity in vitro against relevant C. difficile strains, while avoiding native gut flora. Additionally, the compound was designed to be gut-restricted, with minimal systemic circulation following PO dosing.
Sonrotoclax, BeiGene’s clinical-stage, orally bioavailable, next-generation inhibitor, targets both WT and mutated forms of the Bcl-2 protein by binding within a hydrophobic groove, similar to other inhibitors in its class. Explore this case study to see how sonrotoclax was rationally designed to potency against both WT and mutant Bcl-2 and address the limitations of first-generation inhibitors and more!
Here’s a quick recap of the top business news from October, including major deals, acquisitions, funding rounds, and strategic partnerships. If you missed any updates, here’s your chance to catch up on the most significant developments in the industry.
This article highlights key patents published in September 2024, covering a range of therapeutic targets and mechanisms. It includes Nurr1 and Nur77 modulators for oncology applications, STAT3 inhibitors and CRBN-based STAT3 degraders for modulating STAT3 signaling in cancer, and CDK2 molecular glue degraders for estrogen receptor-positive breast cancer resistant to CDK4/CDK6 inhibitors. Additionally, it features ERAP1 modulators for addressing autoimmune diseases, APOL1 inhibitors for APOL1-mediated kidney diseases, and novel NEK7 inhibitors targeting the NLRP3 inflammasome pathway.
HiberCell recently disclosed the discovery of HC-7366, a potential first-in-class, intentionally discovered, orally bioavailable, potent, selective, small-molecule kinase activator of GCN2. HC-7366 has now progressed to Ph. I trials to treat ccRCC and AML. This case study is a fantastic example of how to mitigate CYP3A4 inhibition and improve oral bioavailability via judicious choice of salt formulation.
