Matt Hesse

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.

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.

Novartis' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data.

Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged, including Nodthera’s ND-0796. In a push for new chemotypes, AZ and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story detailed their efforts to overcome PLD (phospholipidosis), genotoxicity, and hERG inhibition in a non-classical pharmacophore series. The discovery was presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome.

Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with >240M infections and >600K deaths each year, the majority of which are in sub-Saharan Africa. The need for new antimalarials is clear, given that over half of the world's population is at risk of infection, combined with the rise of resistance against current treatments. Novartis has played a key role in this fight and at the ACS Fall 2024 meeting in Denver, CO, they disclosed NVP-FVP954: a novel, fast-acting IV antimalarial for severe malaria.

Staying on top of the latest IP disclosures in drug discovery is no small feat, so we’ve made it easier for you! Our team sifted through thousands of recently published patents to compile a curated list of about 200 significant patent documents in the drug discovery space from September 2024. Each entry is accompanied by detailed annotations to help you quickly grasp the essentials.

BMS-986397 is a potential first-in-class CRBN-based selective CK1α molecular glue degrader. CK1α promotes tumor growth by enhancing MDM2 and MDMX degradation of the tumor suppressor p53. Since AML has a low TP53 mutation rate, activating the p53 pathway is a promising approach; however, p53 activators have faced challenges due to hematological toxicities. Targeting CK1α degradation offers an alternative approach. The BMS team sought to develop a CELMoD® for CK1α degradation. This article outlines the discovery of BMS-986397, as presented at the ACS Fall 2024 meeting in Denver, CO.

Despite the remarkable emergence of HAART in the 1990s, the fight against HIV infection is by no means finished. At the ACS Fall 2024 meeting in Denver, CO, Gilead Sciences presented the structure and discovery story of elunonavir (GS-1156), a novel HIV protease inhibitor with remarkable metabolic stability and a human half-life exceeding two weeks. Based on BMS’ atazanavir, the compound incorporates structural elements inspired by Gilead’s HCV NS5A inhibitor program which led to ledipasvir, as “stabilizer” motifs to avoid the extensive CYP metabolism seen in current inhibitors.

This article highlights the key drug discovery patents published in August 2024, including AKR1C3-dependent KARS (not KRAS!) inhibitors for NRF2/KEAP1-mutated cancers and DHX9 helicase inhibitors of MSI-high tumors. It also covers the development of MK2 degraders for inflammatory diseases and small molecule IL-17A inhibitors that show promise in modulating inflammation. Additionally, we cover Roche’s take on Revolution Medicines’ macrocyclic pan-KRAS inhibitors, which show improved PK profiles, and novel non-hydroxamate LpxC inhibitors for treating Gram-negative bacterial infections.

KEAP1 inhibition/NRF2 activation has been hotly pursued in recent years for immunology indications; however, in oncology, NRF2 degradation has been posited as a novel therapeutic mechanism for specific cancers. Vividion has already disclosed work on covalent KEAP1 inhibitors, but at the recent ACS Fall 2024 meeting, the structure and discovery story of their clinical oral covalent activator of KEAP1 were disclosed, identified through careful analysis of the data from their inhibitor screen.

We know keeping up with the latest developments in drug discovery can be a challenge, so we’ve simplified the process for you. We’ve reviewed thousands of newly published patent documents to bring you a curated list of over 200 key patents released in August 2024. Each entry comes with detailed commentary to help you navigate the content quickly and efficiently.

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

PLX-4545 is an oral CRBN-based molecular glue degrader of IKZF2 in Ph. I trials. It potentially addresses anti-tumor immunity suppression within the TME, critical in checkpoint blocker resistance. Tumors use IKZF2 to regulate the function of regulatory T cells and inhibit effector T cells. IKZF2 depletion in regulatory T cells enhances the anti-tumor response. The discovery and structural data of PLX-4545 were presented by Kevin Freeman-Cook at the ACS Fall 2024 First-Time Disclosures session in Denver, CO. We are reporting the discovery story and its potential impact on immuno-oncology.

BAY 2925976 is a novel oral ARα2C antagonist developed by Bayer for the treatment of OSA (obstructive sleep apnea), a widespread condition affecting nearly one billion people globally. Despite the availability of mechanical treatments like CPAP, poor adherence rates highlight the need for more effective interventions. BAY 2925976 demonstrated a preclinical proof of concept for ARα₂C modulation as a potential therapeutic approach for OSA. In this article, we detail the discovery of BAY 2925976, as highlighted by Michael Hahn at the ACS Fall 2024 First-Time Disclosures session in Denver, CO.

In August 2024, seladelpar (LivdelziTM) became the first FDA-approved selective agonist of PPARδ (peroxisome proliferator-activated receptor δ), following an almost 20-year journey from the original discovery and patent publications. Originally developed by CymaBay in collaboration with Johnson & Johnson, approval was granted to Gilead Sciences following their February 2024 purchase of CymaBay Therapeutics for $4.3B. Seladelpar was approved as a second-line treatment for patients with primary biliary cholangitis.

The recently released WHO INN proposed names list includes the structure and name of Structure Therapeutics’ oral small molecule GLP-1R agonist, aleniglipron (GSBR-1290). Seemingly emerging from a “fast-follower” program based on Chugai/Eli Lilly’s orforglipron, the compound includes an unusual phosphine oxide motif and has shown positive results on plasma glucose levels and bodyweight in a Ph. IIa study.

Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with over 240M infections and >600k deaths each year. Currently, over half of the world population is at risk of infection and with the rise of resistance against current treatments, the need for new antimalarials is clear. At the ACS Fall 2024 conference in Denver, CO, Novartis outlined the structure and discovery story of NVP-IWY357, a novel antimalarial that has no cross-resistance to current drugs and the potential to achieve a single-dose cure.

This article highlights a patent application from Monte Rosa Therapeutics that discloses the biological activity of compounds that act as VAV1 molecular glue degraders, providing a summary of key data for selected molecules disclosed in the patent application.

The 2024 EFMC-ISMC joint conference in Rome was centered around two first time disclosure sessions which revealed the structures and discovery stories of seven drugs covering a range of hot targets and modalities. This article captures the key highlights from the sessions, detailing the structures and targets of the novel molecules presented, including Novartis’ HIF-2α inhibitor and their folate receptor-targeted RLT, as well as the novel chemical matter of AstraZeneca/Mitsubishi Tanabe’s NLRP3 inflammasome inhibitor and a first-in-class MKK4 inhibitor for liver regeneration.

To streamline your review of the patent literature, we've distilled thousands of new documents into a searchable table featuring over 200 selected patents focused on key areas in drug discovery, all published in July 2024. Each patent includes commentary for easier navigation and understanding.

AstraZeneca recently disclosed the structure and discovery journey of their oral small molecule PCSK9 inhibitor, AZD0780, during the ACS Fall 2024 First Time Disclosures session in Denver. Discover how the team identified a fragment hit targeting a previously unexplored pocket, verified its novel mechanism of action, and successfully advanced it into a clinical compound now in Ph. II trials for patients with dyslipidemia.

Arcus Biosciences recently disclosed the structure and discovery story of their oral HIF-2α inhibitor casdatifan (AB521) at the ACS Fall 2024 First Time Disclosures session in Denver. Read on to find out how the team overcame serum shifts and metabolism issues to deliver into the clinic what could potentially be a best-in-class compound, superior to the recently approved inhibitor, belzutifan.

AbbVie’s ABBV-467 is a highly potent, selective MCL-1 (myeloid cell leukemia-1) inhibitor which entered the clinic in 2022 in a Ph. I trial in patients with advanced hematologic cancers. MCL-1 has had a rough time in the clinic with multiple trials being halted or terminated due to cardiac toxicity, which is suspected to be an on-target effect. AbbVie’s approach with ABBV-467 was to target a highly potent/short half-life compound which could induce rapid apoptosis and tumor regressions in a short exposure period before the onset of any adverse events. Is this the end for MCL-1?

Nurix Therapeutics’ NX-1607 is the first oral small molecule inhibitor of CBL-B to enter clinical trials. CBL-B negatively regulates immune activation in T, B, and NK cells; while immune checkpoint inhibitors are often effective, they have limitations, including lack of efficacy in certain cancers, patient variability, and resistance. NX-1607 enhances T cell activation by gluing CBL-B in an inactive conformation and, driven by preclincial data, NX-1607 is currently in a Ph. I trial. This article details its discovery story and initial clincial results, presented at the ACS Spring 2024 meeting.

To help you quickly scan the patent literature, we’ve distilled down thousands of new documents into a searchable table of over 200 selected patents focused on key areas in drug discovery, all published in June 2024. This resource is enriched with detailed highlights on selected molecules targeting high-interest areas such as synthetically lethal Polθ inhibitors, SARM1 inhibitors for neurodegenerative indications, and our best guess at the identity of Gilead’s small molecule GLP-1R agonist GS-4571

RMC-9805 is a first-in-class, covalent KRAS(G12D)(ON) molecular glue inhibitor from Revolution Medicines that uses a cyclophilin A (CypA)-recruiting tricomplex mechanism combined with a finely tuned aziridine covalent handle to inhibit the previously “undruggable” KRAS(G12D) mutant. Read our coverage of the discovery story, disclosed at the AACR 2024 meeting in San Diego, to discover how structural and modeling insights were key to engaging a poorly nucleophilic mutant Asp, how RMC-9805 synergizes with PD-1 inhibitors, and the progress this remarkable compound is making in the clinic.

RMC-6236 is a non-covalent pan-RAS(ON) inhibitor from Revolution Medicines, which shows remarkable efficacy in tumors driven by RAS mutants that were previously considered “undruggable,” such as G12V/D/A/S, G13X, and Q61X. RMC-6236 exerts its action via a “tri-complex” mechanism, gluing RAS to the ubiquitously expressed chaperone protein, cyclophilin A. Our in-depth article covers the presentation given at the AACR 2024 meeting, which outlines the discovery and preclinical profile of RMC-6236 as well as the latest clinical updates.

Drug Hunter has sifted through news articles, press releases, financial disclosures, SEC filings, and more to bring you a roundup of 2023’s biggest mergers and acquisitions (M&A) in the drug discovery world. Following our open-access industry overview, in the final installment of this four-part series we bring you the biologics-focused deals opening checkbooks in 2023.

Drug Hunter has sifted through news articles, press releases, financial disclosures, SEC filings, and more to bring you a roundup of 2023’s biggest mergers and acquisitions (M&A) in the drug discovery world. In part 3 of this 4-part series, we bring you the top-ranked small molecule-focused deals by value. Covering a range of targets and modalities, this article gives Drug Hunter members in-depth background and analysis of the hottest science opening checkbooks in 2023.

Drug Hunter has sifted through news articles, press releases, financial disclosures, SEC filings, and more to bring you a roundup of 2023’s biggest mergers and acquisitions (M&A) in the drug discovery world. Following our open-access industry overview, in part 2 of this 4-part series we bring you the small molecule-focused deals, ranked 11-20 by value. Covering a range of targets and modalities, this article gives Drug Hunter members in-depth background and analysis of the hottest science opening checkbooks in 2023.

Drug Hunter has sifted through news articles, press releases, financial disclosures, SEC filings and more to bring you a roundup of 2023's biggest mergers and acquisitions (M&A) in the drug discovery world. In this 4-part series we will give you an open-access overview of the M&A landscape, and then for Drug Hunter members in the coming weeks, we will be providing in-depth coverage and analysis of the small molecule-focused (parts 2 & 3) and biologics-based deals (part 4). This premium content includes background on the targets, chemical/biological matter and clinical data driving these deals.

As part of our "Molecules of the Month" and "Molecule Roundup" series of articles, which bring you the most interesting drug discovery molecules published each month, by member request, we have brought together recently highlighted molecules into a single searchable table. This tool allows you to see longer term-industry trends in therapeutic areas, target selection and chemical matter to inspire ideas for your drug discovery pipeline.

In April 2024, patent disclosures continued to highlight the swift progress in targeting key therapeutic areas. The Drug Hunter team has carefully compiled a searchable database containing over 200 patents relevant to drug discovery. This resource is enhanced with detailed annotations and highlights some of the most promising molecules and targets, such as GPR84 antagonists, brain-penetrant TYK2 inhibitors, and tricyclic urea JAK2 V617F inhibitors, among others. This compilation serves as a valuable tool for drug hunters to stay abreast of the latest trends in drug discovery.

PRMT5 is an epigenetic “synthetic lethality” target that has attracted much attention among drug hunters. The first generation of PRMT5 inhibitors was limited by systemic toxicities resulting in a cooling of industry interest, until the recent identification of tumor-specific inhibitors. These second-generation compounds target the MTA:PRMT5 complex in MTAP-deleted cancers—15% of all tumors—leading to a revival of the target. Read on to find out which companies are prevailing in the search for a first-in-class PRMT5 inhibitor and how their clinical compounds differentiate.

In March 2024, the landscape of patent disclosures continued to reflect the rapid pace of advances against key therapeutic targets. The Drug Hunter team has curated a searchable database encompassing over 200 patents pertinent to the field of drug discovery. This resource is further enriched with insightful spotlight on some of the most promising molecules and targets, including OX2R agonists, TEAD covalent inhibitors, NaV1.8 inhibitors, and selective PI3Kγ inhibitors, among others. This round-up provides a valuable tool for drug hunters to navigate the most recent trends in drug discovery.

Minipigs have recently gained prominence as an alternative non-rodent in vivo model for pharmacokinetic (PK), efficacy, and toxicology studies supporting human dose predictions. This article provides an overview of the use of minipigs in small molecule preclinical drug discovery research, tracing their historical background and outlining practical considerations for selecting them in studies focusing on hepatic metabolism, oral bioavailability, CNS penetration, and toxicology. It highlights minipigs' unique advantages and makes a compelling case for their continued use in preclinical research.

The "New Drugs on the Horizon" sessions at the AACR Annual Meeting 2024 in San Diego revealed twelve innovative oncology agents and offered attendees a first look at their structures and preliminary data as they enter/progress in the clinic. In case you missed any of these exciting compounds – including selective CDK inhibitors, molecular glues, bifunctional degraders, a radiopharmaceutical, a bifunctional antibody, and an ADC – this article covers the structures and targets disclosed. A separate session disclosed the structure of a pan-RAS isoform inhibitor with remarkable clinical results.

February 2024 saw numerous notable patent disclosures aimed at a variety of therapeutic targets across different disease areas. The Drug Hunter team has compiled a searchable table that includes more than 200 patents of relevance to the drug discovery industry. Accompanying the table are detailed notes, as well as standout features from some of our top picks, including MTA-cooperative PRMT5 inhibitors, heterobifunctional TYK2 degraders, strategies for engaging and reactivating mutant p53, and more.

Nrf2/KEAP1 modulation has been pursued since the discovery that dimethyl fumarate and its metabolite protect CNS neurons via up-regulation of Nrf2-depdendent activities. Compounds with greater selectivity have been sought for many years, culminating with the approval of the KEAP1 inhibitor, omaveloxolone. Vividion disclosed their efforts to identify the covalent KEAP1 inhibitor, VVD-702. This ACS Spring 2024 disclosure is an excellent case study for covalent hit finding using chemoproteomics, covalent compound optimization, and the use of an uncommon but surprisingly stable covalent warhead.

The highly anticipated First Time Disclosures session at the ACS Spring 2024 Meeting in New Orleans, organized by Nicole Goodwin and H. Rachel Lagiakos, presented a variety of new orally available small molecules. In case you missed any of these exciting molecules, from Oric’s CD73 inhibitor to Deciphera’s first-in-class ULK1/2 inhibitor, this article provides the structures and targets for the novel molecules disclosed at the session.