Top 12 Most Popular Drug Hunter Case Studies of 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. KRAS inhibitors were of broad industry interest this year with fascinating molecules like divarasib, adagrasib, LUNA18, and BI-2493 making headlines. BTK inhibitors and degraders have moved out of cancer and into chronic immunological and neurological indications, and drugs targeting chemokine receptors like CCR4 and CCR6 are of increasing interest. 

In case you missed these stories, here are the top 12 most popular Drug Hunter case studies published in 2023:

1. Divarasib: Great Timing for Positive Data Makes This KRAS Inhibitor a Big Deal

Genentech’s divarasib (GDC-6036) is a covalent inhibitor of KRASG12C in Ph. III in patients with non-small cell lung cancer (NSCLC), making the molecule the third most advanced KRASG12C inhibitor after the accelerated approvals of Amgen’s sotorasib and Mirati’s adagrasib. 

Recently, data from divarasib’s Ph. I study showed surprisingly strong efficacy, positioning the drug at a pivotal moment following Amgen’s recent regulatory setback with sotorasib and BMS’s timely $5B+ acquisition of adagrasib and Mirati. Read the article to learn more about how this influential molecule was discovered.

2. The Highly Potent and CNS-Active NX-5948 Shows BTK Degradation in Patients 

Nurix recently unveiled their second clinical BTK degrader, NX-5948, which is in Ph. Ia/Ib for patients with advanced B-cell malignancies. A novel CRBN ligand was developed to remove IKZF1/3 degradation activity, distinguishing NX-5948 from Nurix’s earlier disclosed dual BTK-IKZF1/3 degrader, NX-2127, which is currently in Ph. I for relapsed/refractory B-cell malignancies. 

The potent BTK degrader NX-5948 has displayed limited CNS penetration preclinically, yet was found to be highly CNS active thanks to catalytic degradation, allowing for primary CNS lymphoma (PCNSL) participants to be included in the clinical study. The molecule also shows efficacy in an arthritis mouse model, which may enable BTK degraders to be studied outside of oncology as well, such as in multiple sclerosis. This article recaps how Nurix identified this potentially best-in-class BTK degrader, how it differentiates from its cousin, NX-2127, and other BTK programs, and what’s notable about its chemistry and pharmacology.

3. Fenebrutinib: A Reversible, CNS-Active BTK Inhibitor for MS

Genentech recently announced that fenebrutinib (GDC-0853), a noncovalent Bruton’s tyrosine kinase (BTK) inhibitor, rapidly reduced new brain lesions in Ph. II clinical trials for relapsing multiple sclerosis (RMS) and that the molecule would be entering Ph. III, though it was recently placed on clinical hold due to liver enzyme elevations seen broadly with BTK inhibitors in MS.

Following the success of BTK inhibitors in oncology, BTK has been a hotly pursued target to treat chronic autoimmune diseases, with multiple companies evaluating BTK inhibitors in a range of clinically and commercially important indications. Other candidates for MS are all covalent BTK inhibitors, leaving fenebrutinib as the only noncovalent inhibitor in late clinical evaluation. Fenebrutinib’s apparently superior selectivity and safety profile, combined with it having the highest potency of all BTK inhibitors in Ph. III clinical trials for MS, have pulled it ahead of covalent competitors as a potential treatment for rheumatoid arthritis, systemic lupus erythematosus, and MS. This article reviews fenebrutinib’s discovery and decade-plus development, as well as the molecule’s unique properties including its long residence time and brain penetration in humans.

4. A Potential Best-in-Class KRASG12C Inhibitor? The Science Behind How Adagrasib Differentiates from Sotorasib 

Mirati’s “Breakthrough” KRASG12C inhibitor, adagrasib, was granted accelerated approval by the FDA in 2022. As it follows Amgen’s first-in-class KRASG12C inhibitor, sotorasib, adagrasib is constantly scrutinized for any evidence it may be different, or better, than sotorasib. 

This deep dive reviews the current understanding on the difference between adagrasib and sotorasib including whether adagrasib is really CNS-penetrant, what properties would make adagrasib more CNS-penetrant than sotorasib, why adagrasib appears to be less hepatotoxic with immunotherapy, and more.

5. MK-0616: "I Was Told... an Oral PCSK9 Inhibitor is Impossible"

The Merck macrocyclic peptide PCSK9 protein-protein interaction (PPI) inhibitor, MK-0616, is a once-daily PCSK9-lowering and LDL-cholesterol-lowering small molecule that has recently demonstrated antibody-like efficacy as an oral agent in the clinic. 

The program highlights numerous technical achievements at the forefront of modern drug discovery, including mRNA display screening and the use of lipidic permeation enhancer formulations, and will set a standard for modern “classics in drug discovery” for some time. Read the article to learn how Merck developed what was believed to be an impossible oral PCSK9 inhibitor.

6. LUNA18: A Clinical, Oral, Cell-Penetrant, Reversible, Macrocyclic Peptide Pan-RAS Inhibitor from mRNA Display

LUNA18 is an orally bioavailable, cell-penetrant, macrocyclic peptide pan-RAS inhibitor intended for the b treatment of KRAS-mutant cancers. It disrupts the protein-protein interaction between KRAS and SOS, preventing RAS activation. 

The molecule is an important proof-of-concept for macrocycles because it is an example of a clinical candidate derived from peptide mRNA display technology in which a scaffold hop to a non-peptidic core was not required. Eliminating that requirement greatly enhances the scope of mRNA display as a tool for ligand discovery. Continue on to the article to learn how this cell-penetrant and intrinsically orally bioavailable molecule was discovered.

7. Vorasidenib: A Brain-Penetrant mIDH1/2 Inhibitor with Stunning Efficacy in Glioma

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. 

Daily oral dosing of vorasidenib increased progression-free survival (PFS) by a median time of more than 2 years. This delayed disease progression is especially meaningful to patients with low grade gliomas (LGG) since they are often younger than most cancer patients and being able to delay chemo- and radiation therapy until their bodies are more mature can be hugely beneficial. Read the article to learn the science behind this brain-penetrant molecule with a big impact in oncology, including its unique mechanism of action, beautiful binding mode, and human CNS activity validated in tumor samples.

8. Why Is The pan-KRAS Inhibitor, BI-2493, A Big Deal?

Boehringer Ingelheim recently disclosed a pair of pan-KRAS inhibitors in Nature – BI-2865 and in vivo tool BI-2493, which was derived from previously disclosed covalent molecule BI-0474. These two molecules not only inhibit the successfully targeted KRASG12C mutant, but also 17/23 of the most common KRAS mutants including G12A/C/D/F/V/S, G13C/D, V141, L19F, Q22K, D33E, Q61H, K117N, A146V/T, as well as WT KRAS, while sparing NRAS and HRAS. 

BI-2493 has sufficient PK properties to achieve in vivo activity at oral doses of 10-90 mpk BID in mice without toxicity as measured by body-weight loss. Read the article to learn about this important proof-of-concept molecule that has set the stage for tackling RAS with new modalities like targeted protein degradation or tricomplex inhibition.

9. RPT193: A Small Molecule Competing With Biologics in Immunology

RPT193, an oral, second-generation CCR4 inhibitor from RAPT Therapeutics, is in Ph. II clinical trials (400 mg QD) to treat atopic dermatitis (AD) and asthma.

CCR4 has been a long outstanding therapeutic target for treating inflammatory diseases, but despite many efforts, no molecule inhibiting this receptor has progressed beyond Ph. I for these indications. Read about the interesting development of this oral zwitterionic drug, which is a great example of a small molecule that could compete in immunology.

10. A Next-Generation Mutant-Selective PI3Kα Allosteric Inhibitor with a Potentially Improved Safety Profile

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant phosphatidylinositol-3 kinase α (PI3Kα), targeting a cryptic pocket near the ATP-binding site.

PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects. Read the article to learn about how this groundbreaking PI3Kα inhibitor was discovered.

11. Omaveloxolone: A Billion-Dollar Natural Product-Derived Reversible Covalent Nrf2/KEAP1 Modulator

This year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Reata’s lead molecule, omaveloxolone (SKYCLARYS®), is an oral, reversible covalent inhibitor of the E3 ligase KEAP1. The molecule was recently the first drug approved for the treatment of Friedreich’s ataxia (FRDA), a genetic, progressive neurodegenerative disorder caused by impaired signaling of the Nrf2 transcription factor.

KEAP1 ubiquitinates Nrf2, leading to its proteasomal degradation. Inhibition of KEAP1 by omaveloxolone leads to Nrf2 accumulation and functional activation, compensating for the genetic deficiency. This article highlights the origins of this natural product-derived drug in academic research three decades ago, and the elucidation of its mechanism of action involving the important KEAP1/Nrf2 axis.

12. PF-07054894: A Squaramide-Containing, Insurmountable CCR6 Antagonist for Ulcerative Colitis

PF-07054894 is a potential first-in-class, oral Ph. I clinical candidate targeting the chemokine receptor CCR6 for ulcerative colitis. 

Several companies have pursued antibodies and small molecules targeting CCR6 or its endogenous ligand, CCL20 for immunological conditions, but PF-07054894 appears to be the first selective CCR6 antagonist to enter clinical development. Read this article to learn about how this molecule emerged from a structure-based drug discovery program from a squaramide scaffold with history in CXCR2 modulation, and how the molecule features insurmountable antagonism of CCR6, but surmountable antagonism of CCR7 and CXCR2.

Drug Hunter Molecule Case Studies are a great way to find transferable insights from other companies’ programs in areas outside of your current project or focus area. You can find hundreds of others using the full-text search or chemical structure search.