September’s Molecules of the Month include Genentech’s HPK1 inhibitor for cancer immunotherapy and Novo Nordisk’s CB1 receptor inverse agonist for metabolic disorders. We also feature TAK-861, Takeda’s highly selective OX2R agonist, which has entered a pivotal Ph. III trial. Other notable molecules from September include a small molecule IL-17 inhibitor from Novartis and Boehringer Ingelheim’s pan-KRAS heterobifunctional degrader.
You can read more about the compounds that made our September 2024 Molecules of the Month list and check out recent articles for each, linked below:
GNE-6893 – An orally bioavailable selective isoquinoline-based HPK1 (hematopoietic progenitor kinase 1, MAP4K1) inhibitor from Genentech designed to enhance TCR (T cell receptor) signaling identified through fragment-based screening and structure-based drug design. GNE-6893 demonstrates subnanomolar potency, high kinase selectivity (347/356 kinases unaffected at 0.1 μM), and favorable pharmacokinetics. Numerous companies have started HPK1 programs, including Nimbus, Genentech, Merck, BMS, Pfizer, Bayer, Incyte, Daiichi Sankyo, and others. However, many inhibitors of HPK1 have “bell-shaped” pharmacology. A key breakthrough here was using curve width in a primary human T cell IL2 assay to optimize kinase selectivity and enhance TCR signaling. Additionally, this work highlights the strategic use of N-aryl-O-alkyl carbamates as amide isosteres to achieve favorable physicochemical properties.
monlunabant – Novo Nordisk’s CB1 receptor inverse agonist, monlunabant, demonstrated significant weight loss in a Ph. IIa trial (NCT05891834). The lowest dose (10 mg QD) yielded the greatest effect, with participants losing an average of 7.1 kg. Acquired through a $1B acquisition of Inversago Pharma in 2023, monlunabant targets peripheral CB1 receptors to reduce appetite and metabolism issues while minimizing psychiatric side effects seen with rimonabant. However, mild to moderate neuropsychiatric side effects, including anxiety and sleep disturbances, were reported. A Ph. IIb trial is planned for 2025 to optimize dosing and safety.
BIO-2007817 – A small molecule allosteric modulator that enhances parkin activity, crucial for mitigating mitochondrial dysfunction in early-onset Parkinson’s disease. Acting as a molecular glue, the closely related compound BIO-1975900 was found to bind near pUb (phospho-ubiquitin) on parkin’s RING0 domain, facilitating activation by releasing the catalytic Rcat domain. Structural studies, including crystallography and hydrogen-deuterium exchange mass spectrometry, confirmed this mechanism. In mitophagy assays, BIO-2007817 partially restored function in parkin mutants (R42P and V56E), suggesting these modulators hold promise as therapeutic agents for EOPD.
TAK-861 (oveporexton) – In February, Takeda announced topline results from a Ph. IIb trial (NCT05687903) for TAK-861, an oral, potent, and highly selective OX2R (orexin receptor 2) agonist, demonstrating significant improvements in wakefulness among individuals with NT1 (narcolepsy type 1) with no treatment-related serious adverse events. It activates OX2R with an EC50 of 2.5 nM and promotes wakefulness at doses as low as 1 mg/kg in mice and monkeys, demonstrating tenfold higher potency than TAK-994. Compared to modafinil (ProvigilTM), it shows broader brain-wide neuronal activation, indicating efficient wake-promoting effects while aiming to mitigate the liver toxicity observed with TAK-994. TAK-861 is currently in a Ph. III trial (NCT05816382).
YK-2168 – A novel selective CDK9 inhibitor from an azaindole series designed to overcome the toxicities seen with other CDK9 inhibitors like AZD4573 and BAY1251152. SAR studies led to the identification of YK-2168, which demonstrated improved CDK9 selectivity and solid tumor efficacy in a gastric cancer model (SNU16 CDX). It also shows a clean safety profile in preclinical GLP safety studies and exhibits a differentiated IV PK profile. YK-2168 is currently under clinical development in China (CTR20212900) for cancer treatment.
TCMCB07 – A melanocortin-4 receptor antagonist that shows promise in preclinical models by mitigating chemotherapy-induced anorexia and weight loss. When administered peripherally, it improved appetite, stabilized body weight, and preserved fat and heart mass across multiple chemotherapy regimens. Additionally, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced its effectiveness. Importantly, no significant adverse effects or increased toxicities were observed. These findings suggest that TCMCB07 could offer a novel therapeutic strategy to improve the quality of life for patients undergoing chemotherapy.
ACBI3 – A potent, injected pan-KRAS heterobifunctional degrader designed to overcome the challenges of targeting KRAS mutations beyond G12C and also serves as a proof-of-concept for pan-KRAS degradation. Through structure-based optimization of a VHL:heterobifunctional degrader complex, ACBI3 achieves broad mutation coverage (13 out of 17 of the most prevalent oncogenic KRAS mutations), leading to robust suppression of MAPK signaling and tumor regression in preclinical models. Unlike traditional inhibitors, it employs ubiquitin-mediated degradation, resulting in over ten-fold higher potency. Interestingly, the authors report that mice developed skin lesions when ACBI3 was formulated with PEG-400/Transcutol/Kolliphor HS 15 and administered subcutaneously. As a result, they switched to intraperitoneal delivery using a nano-milled suspension formulation. For a deeper dive into KRAS research and discoveries, check out our comprehensive coverage here.
TYRA-300 – Tyra Biosciences’ potent, selective, and orally bioavailable FGFR3 (fibroblast growth factor receptor 3) inhibitor designed to avoid the toxicities associated with pan-FGFR inhibitors like erdafitinib, which suffer from off-target toxicities and resistance mutations. Another essential goal for this program was to meet the safety standards required to progress into pediatric populations for the treatment of ACH (achondroplasia) and other skeletal dysplasias. ACH, the most common form of dwarfism, occurs in approximately 99% of cases due to a specific G380R mutation in FGFR3. Designed using a structure-based approach, TYRA-300 targets FGFR3 and remains effective against FGFR3 gatekeeper mutations. TYRA-300, whose structure and discovery story were recently disclosed at the ACS Fall 2024 meeting, is currently in Ph I clinical trials (NCT05544552) for advanced urothelial cancers and other solid tumors, with plans to expand into Ph. II studies.
losmapimod – Fulcrum Therapeutics' losmapimod, once a promising first-in-class treatment for FSHD (facioscapulohumeral muscular dystrophy), failed its pivotal Ph. III trial (NCT05397470). Licensed from GSK in 2019 and backed with a recent $80M investment from Sanofi, this p38ɑβ MAPK inhibitor aimed to reduce DUX4 gene expression, the key driver of FSHD. However, it showed no significant improvement in RSA (relative surface area), a measure of RWS (reachable workspace), after 48 weeks compared to placebo. As a result, Fulcrum halted further development of losmapimod in FSHD.
compound 26 – A small molecule IL-17 inhibitor from Novartis that was developed in an effort to address the potential toxicology risks linked to the furazan moiety in the discontinued IL-17 inhibitor LY3509754. In a market largely dominated by IL-17A antibodies for autoimmune and inflammatory diseases, the quest for small molecule inhibitors of IL-17A signaling has been the aim of a number of companies (e.g., UCB, Leo Pharma) over recent years. Compound 26, an α-fluoro-acrylamide analog of LY3509754, showed promising efficacy by reducing knee swelling in a rat arthritis model. However, early toxicity studies in rats and dogs revealed adverse effects, indicating that the furazan moiety may not have been responsible for LY3509754’s toxicity. As a result, compound 26 and its analogs were not pursued further for development.
Reviewer Commentary from Charles Cole
Given the widespread success of immune checkpoint inhibitors, it’s no surprise that most companies have pursued combination therapies to enhance the already profound efficacy of these therapeutic agents. Recent studies have suggested that HPK1 may provide one such avenue given its negative regulatory role within the immune system, whereby activation of HPK1 results in reduced T cell receptor signaling, and therefore its inhibition may provide a heightened immune response to cancer cells. In this work, Genentech shares its own approach to the development of such a small molecule inhibitor of HPK1. While the story begins with a standard SPR fragment screen to identify a desirable core from which to build, followed by confirmation of biochemical and cellular potency, things begin to get more complex when looking at the secretion of IL-2 as a downstream marker for successful HPK1 inhibition. Quite interestingly, the authors note the appearance of a bell-shaped dose-response curve that causes several concerns. First, it implies that reaching maximal T cell activation throughout dosing would be non-trivial, and, further, they found that at higher doses IL-2 could be suppressed below initial concentrations, implying the molecule was serving as a kind of immuno-suppressant. They postulate that off-target kinase activity may be the issue, wherein the inhibitor binds to a different kinase which serves a positive regulatory role within the immune system. Given that no clear culprit could be identified despite extensive screenings, which in turn rules out the ability to design around specific kinases, the authors apply an ingenious proxy for overall selectivity: the width of the dose-response curve. With this metric in hand, medicinal chemistry efforts were initiated to achieve potency, selectivity, metabolic stability, and oral bioavailability to arrive at GNE-6893. This story provides an alternate, and interesting, way to gauge selectivity, and I look forward to future disclosures with demonstrated IVIVCs to further validate these potency and selectivity metrics.
Reviewer Commentary from Julien Lefranc
Genentech’s paper on the hottest immuno-oncology target is excellent. Genentech showed a very smart way to use bell-shaped IL2 curves to assess the overall kinase selectivity of their compounds and identified a compound with a maximized effect on IL-2 secretion.
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