Rory McAtee

Tyra Biosciences’ lead asset, TYRA-300, is a potent, selective, and orally bioavailable FGFR3 inhibitor designed to mitigate the toxicities commonly seen with pan-FGFR inhibitors. A key objective of the program was to meet the safety standards required for advancing into pediatric populations for the treatment of ACH (achondroplasia) and other skeletal dysplasias. TYRA-300 is currently being evaluated in Ph. I clinical trials for advanced urothelial cancers and other solid tumors and, importantly, has received IND clearance to initiate a Ph. II clinical trial in pediatric ACH patients.

GSK and Roche strengthened their pipelines by forming groundbreaking collaborations that target neurodegenerative diseases and transcription factors, respectively. Meanwhile, Pep2Tango Therapeutics introduced a novel obesity treatment approach, and Amgen faced scrutiny over emerging data on its obesity drug candidate MariTide. This roundup covers the details behind these headlines.

This summary of major clinical updates from November 2024 covers FDA approvals, the initiation of new clinical trials, notable trial outcomes for key drug candidates, and news on paused and discontinued trials and programs.

HRX-215 is an orally bioavailable MKK4 inhibitor for liver regeneration. In just over a decade since they discovered the dual specific kinase MKK4 as a master regulator of hepatocyte regeneration, HRX-215 completed a FIH clinical trial. This article is a fascinating case study on harnessing the liver's natural regenerative capacity, identifying key regulators of liver regeneration, and leveraging a kinase inhibitor with reported off-target activity for MKK4 as a suitable starting point, among other insights.

IAG933 is Novartis’ potential first-in-class small molecule inhibitor of the PPI between YAP/TAZ and TEAD, currently in a Ph. I trial for solid tumors with Hippo pathway alterations. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to inform hit selection and guide lead optimization, how to employ multiparameter optimization to circumvent cardiotoxicity liabilities, and how to redirect metabolism.

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.

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.

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.

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.

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.

In this article, we present a curated selection of over 60 molecules from September that caught our attention, along with highlights of our top picks and insights into why they stand out.

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.

Sovleplenib (HMPL-523) is an orally bioavailable Syk inhibitor being developed by HUTCHMED and is currently in Ph. II and Ph. III clinical trials for several autoimmune diseases. Derived from an HTS hit and SAR optimization, the discovery story of sovleplenib serves as an excellent case study on how to design a next-generation Syk inhibitor devoid of off-target kinase activity, mitigated hERG activity, and more.

EOS-984 is an oral, potential first-in-class, highly selective ENT1 inhibitor from iTeos currently in clinical trials for advanced solid tumors. The drug, which was identified through SBDD and optimization of the vasodilator dilazep, targets the immunosuppressive effects of adenosine, which helps tumors evade immune detection. This is an excellent case study on the importance of understanding a molecule's bioactive conformation to reduce the entropy of binding and enhance potency.

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.

BMS-986408 is an oral, dual DGK ⍺ and ζ inhibitor currently in a Ph. I/II trial in patients with solid tumors. The compound was identified stemming from a phenotypic screening approach, and subsequent target deconvolution revealed DGK to be the target. If approved, it would be a first-in-class intracellular checkpoint inhibitor of DGK. This is an excellent case study on how to overcome a DILI risk associated with BSEP inhibition, as well as how to improve solubility and PK properties of your compounds through the introduction of polarity, reduction of aromatic rings, and increase in f(sp3).

Arvinas’ ARV-471 is an orally bioavailable CRBN-based ER PROTAC degrader for treating patients with ER+/HER2-breast cancer and the first PROTAC to enter Ph. III clinical trials. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Arvinas’ ARV-471 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

This summary of September's major clinical updates features FDA approvals, drug withdrawals, anticipated regulatory decisions, notable trial results, new NDA submissions, clinical trial setbacks, and the initiation of new clinical trials.

In this article, you'll find a curated selection of >70 molecules from August that piqued our interest, highlights of some of our favorites, and explanations of why they're worth watching.

NDI-101150 is an oral HPK1 inhibitor discovered by Nimbus Therapeutics and is currently in Ph. I/II clinical trial in advanced solid tumors. HPK1 is a compelling immuno-oncology target due to its critical role in regulating T-cells, B-cells, and dendritic cell-mediated immune responses. HPK1-deficient mice demonstrate enhanced anti-tumor T-cell responses and resistance to tumor growth. In this article, we detail the discovery of NDI-101150, as highlighted by Nimbus at the ACS Fall 2024 First-Time Disclosures session, interim results from the clinic, and more.

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.

During Drug Hunter’s Flash Talks, experts talk in-depth about hot topics in drug discovery. These experts also share insights beyond the subjects of their presentations, such as how they got inspired to become a drug hunter, what their favorite molecule is, what excites them most in drug discovery today, and what advice they wish they could give their younger selves. Here is a quick look at some of these insightful nuggets from Flash Talks hosted between January and August 2024.

Pfizer disclosed the structure and discovery of their oral small molecule BDK inhibitor/degrader, PF-07328948, during the ACS Fall 2024 First-Time Disclosures session in Denver. The team identified a thiophene carboxylic acid-based hit targeting an allosteric pocket on BDK. Through optimization, they overcame challenges such as potential IADRs and BDK-E2 complex stabilization. By manipulating the dihedral angle of the methoxy group, they enhanced binding interactions, verifying PF-07328948's unexpected mechanism of action in vivo. PF-07328948 is currently Ph. I trials.

In case you missed August’s business news, here’s a quick recap of five headlines, including an acquisition, three funding rounds, and a notable company closure.

Here’s a rundown of August’s key clinical developments, including FDA approvals, potential upcoming approvals, notable trial readouts, new NDA submissions, and pipeline realignments.

This article highlights a patent application from Constellation Pharmaceuticals that discloses the biological activity of compounds that act as TREX1 inhibitors, providing a summary of key data for selected molecules disclosed in the patent application.

This article highlights a patent application from AstraZeneca and Mitsubishi Tanabe, and Astellas Pharma that discloses the biological activity of compounds that act as NLRP3 inhibitors, providing a summary of key data for selected molecules disclosed in the patent application.

This article highlights a patent application from Arvinas that discloses the biological activity of compounds that act as tau-targeting heterobifunctional degraders, providing a summary of key data for selected molecules disclosed in the patent application.

This article highlights a patent application from Puhe BioPharma that discloses the biological activity of compounds that act as WRN helicase inhibitors, 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.

The INN Proposed List 131, released on August 11th, 2024, unveils the latest batch of drug names currently under consideration by the WHO. To streamline your review, we’ve distilled and compiled a searchable table for the small molecules that includes company identifiers, the newly proposed drug names, structural information, original patents, companies, and mechanisms of action, including structures that were previously undisclosed.

In this article, you'll find a curated selection of nearly 50 molecules from July that piqued our interest, highlights of some of our favorites, and explanations of why they're worth watching.

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.

Kymera’s KT-413 is a CRBN-based dual-mechanism degrader that degrades both IRAK4 and the transcription factors IKZF1/3, acting as an IMiD, with promising clinical activity for the treatment of ABC-like subtype of DLBCL. This fascinating case study demonstrates how a dual-mechanism degrader of IKZF1/3 and IRAK4 can be designed to maximize NF-κB inhibition while simultaneously upregulating the Type I interferon response. This approach restores the apoptotic response and enables oncogene-mediated cell death, resulting in a robust antiproliferative and pro-apoptotic effect in MYD88 mutants.

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2. This Featured Case Study reviews how it was discovered, how it works, and why it matters.

The highly anticipated First Time Disclosures session, attended by over 400 conferees, both in-person and virtually, was organized by the MEDI Division of ACS at the ACS Fall 2024 meeting in Denver. This session unveiled 13 fascinating small molecules currently in clinical development. The two-part event showcased innovations ranging from Novartis’ pentafluorosulfanyl-containing antimalarial, IWY357, to Vividion’s covalent activator of KEAP1, which targets NRF2 degradation. This article captures the essence of the session, providing the structures and targets of the novel molecules disclosed.

Kymera's KT-474 is the first oral heterobifunctional degrader to demonstrate activity in clinical trials outside cancer. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Kymera's KT-474 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

BMS-986365 is a potential best-in-class heterobifunctional ligand-directed degrader of WT AR. This full case study details how this heterobifunctional degrader was engineered to have low intrinsic agonism and exert direct antagonism of WT AR through occupancy of its ligand-binding domain, how the dual modality of BMS-986365 results in deep AR pathway inhibition and allows antagonism to reinforce degradation to combat compensatory resistance mechanisms, its attractive preclinical profile, interim clinical data, how it differentiates from Arvinas’ first-to-clinic AR degraders, and more!

Nested Therapeutics’ lead asset, NST-628, is an oral, brain-penetrant pan-RAF–MEK non-degrading molecular glue that lacks paradoxical pathway activation. Read the full article to learn about NST-628’s fascinating mechanism of action preventing paradoxical pathway activation, how it differentiates from other RAS/RAF/MAPK pathway inhibitors, the likely molecular origin, preclinical profile supporting clinical development, why this might be an ideal combination partner, and why this molecule is a big deal.

To get you up to speed, here’s a recap of July’s molecules on the move, including potential upcoming approvals, key interim trial readouts, new IND submissions, and trial setbacks.

In case you missed anything while you were away on summer holiday, here’s a recap of six notable deals from July to get you up to speed.

If you are as excited as we are about this new era of non-opioid pain management and want to learn more, explore our series of articles that unravel the fascinating history of target validation of voltage-gated sodium channels, showcase the breakthroughs achieved so far, and look forward to what lies ahead for the industry.

Drug Hunter offers industry professionals a faster way to find and absorb the latest research and insights in drug discovery. It is a curated collection of the most relevant and transferable scientific knowledge so you can spend less time weeding through the noise and more time turning molecules into medicines. But we also love hearing from you, the drug hunters in the field.

With increasingly tight timelines between bench and clinic, considering formulation strategies early on can give your program a competitive edge. This succinct formulations guide provides specific clinically-used examples of common formulations, and can help you select a formulation strategy most likely to succeed based on the properties of your compound.