Catalytic Inhibitors Used in Cancer Research

KRAS mutations drive approximately 30% of human cancers, with hotspot mutations at G12, G13, and Q61 positions. Despite the development of KRASG12C-specific inhibitors like sotorasib and adagrasib, resistance inevitably emerges through secondary mutations and bypass signaling. A new study in Cancer Cell presents MCB-294, a pan-KRAS inhibitor, and its derived degrader MCB-36, offering potential solutions to these challenges. Methods: The research team designed MCB-294 with a unique C4-(R)-3-methyl-3-hydroxypiperidine (MHP) moiety that enables binding to both GDP-bound (inactive) and GTP-bound (active) KRAS states. Crystal structures revealed that MCB-294 engages the switch-II pocket through a water-mediated hydrogen bond network connecting conserved residues G10, T58, and Y96. Building on MCB-294, they developed MCB-36 - a PROTAC degrader that conjugates the pan-KRAS warhead to a VHL E3 ligase ligand. The compounds were evaluated across 30+ cancer cell lines, patient-derived organoids, and multiple xenograft models including Apcflox/flox; KrasG12D/+ mice. Results: MCB-294 demonstrated broad activity against KRAS mutants (G12D/C/V/S, G13D, Q61H) with IC50 values ~125 nM in KRAS-dependent cancer cells while sparing normal cells (IC50 >10 μM). The inhibitor showed superior efficacy compared to BI-2865 and maintained activity against sotorasib/adagrasib-resistant cells harboring G12C/Y96C or G12C/H95D mutations. MCB-36 achieved sustained KRAS degradation with half-life reduction from 24h to <6h. Both compounds significantly suppressed tumor growth in PDX models and enhanced antitumor immunity by increasing CD8+ effector T cells while reducing exhausted T cell populations. Combination with anti-PD-1 therapy showed synergistic effects. Conclusions: This study presents a promising therapeutic strategy for broadly targeting KRAS-driven tumors. The water-mediated binding mechanism of MCB-294 provides structural insights for pan-KRAS inhibition, while MCB-36 demonstrates the advantages of targeted protein degradation. Both compounds overcome KRASG12C inhibitor resistance and enhance immune responses, suggesting potential for combination immunotherapy approaches in KRAS-mutant cancers. The dual-targeting mechanism and ability to overcome resistance positions these compounds as valuable additions to the expanding KRAS-targeting therapeutic arsenal. Paper and research by @Juanjuan Feng and larger team

Swedish team discovered mitochondria role in cancer proposing novel treatment approach today. Mitochondria—cellular power plants—have central but underappreciated roles in cancer development. Swedish researchers at Uppsala University discovered that cancer cells modify mitochondrial function enabling unrestricted proliferation while evading immune detection. Targeting cancer-specific mitochondrial adaptations offers novel therapeutic approach converting cancer's metabolic advantage into vulnerability. The mechanism involves cancer cells reprogram mitochondrial metabolism through mutations in mitochondrial DNA and altered metabolic enzyme expression. These changes enable rapid energy production supporting hyperproliferation while generating metabolic byproducts suppressing immune recognition. Cancer cells essentially hack mitochondrial machinery for survival advantage. This mitochondrial addiction creates opportunity: target cancer-specific metabolic dependencies. Researchers identified metabolic inhibitors specifically targeting cancer mitochondria: drugs blocking succinate dehydrogenase, blocking electron transport chain complex I, or blocking mitochondrial calcium handling. These inhibitors selectively kill cancer cells dependent on altered mitochondrial metabolism while relatively sparing normal cells with standard metabolism. Early trials treating 67 cancer patients showed 42% objective response rate—meaningful for previously treatment-resistant disease. The elegant part involves combining mitochondrial-targeting drugs with immune checkpoint inhibitors: removing mitochondrial-dependent metabolic immunosuppression allows immune systems to attack cancer simultaneously targeted at metabolic level. Dual targeting—metabolism plus immunity—overcomes compensatory mechanisms enabling survival. Beyond cancer, mitochondrial dysfunction underlies aging, neurodegeneration, and metabolic disease. Understanding cancer-induced mitochondrial changes reveals how metabolism drives age-related disease. Interventions targeting mitochondrial dysfunction could simultaneously benefit cancer prevention and aging reversal—suggesting mitochondrial function is fundamental to healthy aging. Source: Uppsala University, Cell Metabolism 2025.

A notable theme emerging from #AACR2026 is that the RAS field is already moving beyond first-generation inhibition toward next-generation catalytic control. Revolution Medicines’ clinical data with daraxonrasib in advanced pancreatic cancer have understandably drawn significant attention, particularly the stronger activity being seen in earlier-line and combination settings. Equally intriguing, however, is the company’s preclinical presentation of RM-055, described as a novel catalytic inhibitor designed not only to suppress RAS signaling, but to actively shift RAS from its “on” to its “off” state. Conceptually, this is important. If borne out, such an approach could address one of the central challenges in targeted therapy: adaptive resistance, including amplification of mutant RAS. A compound capable of catalytically driving multiple RAS molecules into the inactive state may represent a meaningful advance over agents that primarily block signaling output. The broader message is clear: the RAS field is evolving from inhibition alone toward deeper mechanistic control, and from monotherapy toward rational combination strategies such as TEADi, Her2ADC, and IO. In pancreatic cancer especially, the implications could be substantial if earlier intervention, improved response rates, and ultimately conversion to surgical candidacy become achievable. It is still early, and the preclinical findings will need rigorous validation in the clinic. But taken together, these developments suggest that RAS-directed therapeutics are entering a more sophisticated and potentially more impactful phase.

As our Drug Hunter team was compiling the November Molecule Roundup, one molecule that really caught our attention was Compound 4—a mutant-selective, salicylaldehyde-based covalent inhibitor designed to target the AKT1 (E17K) oncogenic mutation. This discovery, reported in collaboration between Jack Taunton’s group at University of California, San Francisco and Terremoto Biosciences in Nature Magazine, addresses a mutation frequently observed in solid tumors, where it drives persistent oncogenic signaling via constitutive membrane localization. What makes Compound 4 stand out to me is its design strategy. Unlike traditional pan-AKT inhibitors, which are often plagued by dose-limiting hyperglycemia, Compound 4 leverages a unique allosteric, lysine-targeted mechanism to achieve exceptional selectivity for AKT1 (E17K) over wild-type AKT isoforms. Structural analysis uncovered an unexpected twist: the salicylaldimine adduct, formed with the mutant lysine, recruits endogenous Zn²⁺. This zinc ion coordinates with two proximal cysteines in the kinase activation loop, resulting in sustained inhibition of AKT1 (E17K) while leaving wild-type AKT isoforms largely unaffected. The outcome? Robust anti-tumor efficacy in AKT1 (E17K) xenograft models, without inducing the hyperglycemia often seen with traditional inhibitors. What excites me most is the broader potential of this approach. The chelation-enhanced binding mechanism suggests that this strategy could be extended to other proteins with lysines near metal-binding regions, such as metalloenzymes and zinc fingers. This could open entirely new avenues for targeting previously elusive protein classes. What other targets do you think could benefit from this chelation-enhanced strategy? Explore our full November Molecule Roundup here: https://lnkd.in/e6Jsny6A And stay tuned—we’re finalizing our December molecules now!

Here’s How to Prime Tumors to be Defeated by Cancer Immunotherapy UCSF research may green light many more patients for immunotherapy, offering a faster path to remission and relief. The study reexamined immunotherapy clinical trial data on bladder and skin cancer and found that “cold” tumors, ones that haven’t yet been infiltrated by immune cells, are just as vulnerable to checkpoint inhibitors as “hot” tumors, which have. In mice, these cold tumors were defeated with a combination of radiation, immunotherapy and drugs that block a signal, TGF-Beta. Tumors use this signal to evade the immune system. The findings were published on March 6 in the Journal for ImmunoTherapy of Cancer. Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade Results We found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high βAlt, cold mouse and human tumors that responded to ICB. Conclusions These studies indicate that loss of TGFβ signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy. https://lnkd.in/eapunhTE

We are pleased to share our new Nature Communications paper https://lnkd.in/gtfRiM5D entitled “CDK2 Inhibitor BLU-222 Synergizes with CDK4/6 Inhibitors in Drug-Resistant Breast Cancers through p21/p27 Induction,” which describes a mechanistically driven strategy to overcome resistance to CDK4/6 inhibitors in breast cancer. In this study, we demonstrate that selective CDK2 inhibition with BLU-222, particularly when combined with CDK4/6 inhibitors, produces robust and durable tumor regression in models of CDK4/6 inhibitor–resistant HR+/HER2− breast cancer and triple-negative breast cancer, clinical settings where therapeutic options are limited, and resistance is nearly universal. What distinguishes this work is the mechanistic insight into how CDK2 inhibition rewires resistant tumors. We show that BLU-222 restores endogenous cell-cycle control by inducing the CDK inhibitors p21 and p27 and converting them into obligate suppressors of both CDK2 and CDK4 activity. This dual engagement collapses compensatory proliferation programs, enforces durable cell-cycle arrest, and drives replication stress–associated senescence, accompanied by interferon and immune-associated signaling. Importantly, genetic loss of p21 or p27 abolishes therapeutic synergy, establishing these proteins as essential mediators of response rather than passive biomarkers. Why this work matters clinically: • Establishes a mechanistically grounded approach to overcome CDK4/6i resistance by restoring endogenous cell-cycle control • Identifies p21 and p27 induction and engagement as actionable pharmacodynamic markers to guide dosing and on-treatment assessment • Provides a strong preclinical rationale for CDK2–CDK4/6 combination trials in HR+/HER2− and triple-negative breast cancer • Offers a framework for trial design, patient monitoring, and response stratification in next-generation cell-cycle–directed therapies I am also especially grateful for the highly interactive and scientifically rich collaboration with Blueprint Medicines. This work reflects a model academic–industry partnership—defined by open dialogue, hypothesis-driven iteration, and a shared commitment to mechanistic clarity and clinical translation. Working together in real time allowed us to align biology, drug properties, and trial-relevant questions in a way that meaningfully accelerates impact for patients. This paper reflects what is possible when team science and partnership are placed at the center of translational research. 👏 Huge thanks to all authors Linjie Luo Kelly Hunt Mei-Kuang Chen Sepideh Mohammadhosseinpour Xiayu Rao Yan Wang Jing Wang Saba Kamaliasl Rachel Kim Serena K. Carmen Ulizio Nicole M Kettner, PhD Juliana Navarro Yepes, PhD Kerrie Faia MD Anderson Cancer Center Blueprint Medicines Nature Portfolio #CDK2i #Blu222 #breastcancer #TNBC #CDK4/6

Part 36, From PARP inhibitors to Clinical Reality. The story begins with the discovery of PARP1 in the mid‑1960s, when it was recognized as a DNA‑damage sensor essential for single‑strand break repair, genome stability, and transcriptional regulation. This immediately suggested that blocking PARP would cripple DNA repair, especially in cells already deficient in homologous recombination, such as BRCA1/2‑mutant tumors. PARP detects DNA damage and uses NAD⁺ to build ADP‑ribose chains: the 2′‑hydroxyl of adenosine attacks NAD⁺, releasing nicotinamide as the leaving group. The liberated nicotinamide then re‑binds in the catalytic pocket and inhibits PARP, a classic product‑inhibition loop. Accordingly, nicotinamide, benzamide, and 3‑aminobenzamide were the first PARP inhibitors and served as the medicinal‑chemistry starting point for the entire class. Medicinal chemistry efforts focused on generating more potent, orally available compounds. By around 2000, co‑crystal structures with lead inhibitors had become routine, greatly accelerating structure‑based design. Rucaparib was the first PARP inhibitor to enter human trials, but later showed inferior overall survival in ovarian cancer studies, leading to multiple withdrawn indications and a much narrower clinical role than originally expected. Talazoparib represents the clearest medicinal‑chemistry optimization, with the highest intrinsic activity and the strongest PARP‑trapping potency. Trapping occurs when an inhibitor stabilizes PARP–DNA complexes and prevents the enzyme from dissociating, creating highly cytotoxic roadblocks during replication. Talazoparib is, in some respects, too potent: it induces more DNA damage but also more hematologic toxicity, which limits dose intensity, combination strategies, and long‑term use. Olaparib, approved in 2014, is the most widely used PARP inhibitor worldwide, supported by the strongest clinical evidence across multiple cancer indications, the best survival data, and the most successful combination regimens. This history illustrates that rational design and extensive medicinal chemistry can produce highly potent and selective PARP inhibitors, but that delivering the agent with the best clinical performance ultimately requires considerable luck -specifically, finding the optimal balance between potency, safety, and combinability with other cancer therapies.

Happy to share our collaborative study, led by the Jana Shen Lab, which unravels the mechanism of dimer selectivity and binding cooperativity of BRAF inhibitors using a combination of molecular dynamics simulations and experimental insights. Notably, we highlight the PHI1 inhibitor, developed by our group, which exhibits positive cooperativity, priming the BRAF dimer for enhanced inhibitor binding. https://lnkd.in/egAbiSBv Key findings include: Dimerization reshapes BRAF conformation, stabilizing the αC-helix and increasing DFG flexibility. Hydrogen bond interactions drive dimer selectivity by favoring the αC-in state. PHI1 shows positive cooperativity, preorganizing the opposite protomer for enhanced binding. The study provides a new empirical framework to assess dimer-selective BRAF inhibitors. These insights deepen our understanding of kinase allostery and aid in the design of next-generation RAF inhibitors against mutant BRAF-driven cancers. Excited to see where this leads! Jana Shen Poulikos Poulikakos Evangelia Matenoglou #CancerResearch #BRAF #KinaseInhibitors #ComputationalBiology #DrugDiscovery

Researchers just validated something the oncology community has been watching closely: (A new goldmine for cancer treatment) DHODH (dihydroorotate dehydrogenase) inhibition is a goldmine target for cancer treatment. What makes DHODH special? Unlike most cancer targets that work through single pathways, DHODH inhibition hits cancer cells with a double punch: - Blocks DNA building blocks - Cancer cells need massive amounts of nucleotides to replicate their DNA. DHODH is essential for making these building blocks. - Crashes cellular energy production - DHODH maintains mitochondrial function. Without it, cancer cells can't generate the energy needed for rapid growth. The breakthrough insight from this study: The authors showed that DHODH inhibition selectively targets newly activated T-cells while sparing already-activated ones in-vitro and in xenograft models. Meaning… You can shut down the cancer-driving immune responses while preserving anti-tumor immunity. Why this matters for drug development: The molecule (JBZ-001) worked in this way at oral, nanomolar concentrations Translation: potentially potent activity at low doses that patients can take as pills (not IV infusions). The clinical translation potential: Graft-versus-host disease affects 30-70% of bone marrow transplant patients. Current treatments are broadly immunosuppressive - they prevent GVHD but also increase infection risk and cancer relapse. DHODH inhibition threads the needle: preventing harmful immune reactions while preserving beneficial anti-cancer effects. Watch this space. What do you think?

Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: a proof-of-concept trial A first-in-human study demonstrates that digoxin treatment can partially dissolve circulating tumor cell (CTC) clusters, paving the way for larger studies with enhanced Na+/K+ ATPase inhibitors. - Circulating tumor cells (CTCs) are living cells that are shed from both primary and metastatic lesions into the bloodstream, acting as metastatic pioneers. The presence of CTCs has been firmly established to be predictive of poor prognosis in patients with breast cancer. - In breast cancer, preclinical studies showed that inhibitors of the Na+/K+ ATPase suppress CTC clusters and block metastasis. - The authors conducted a prospective, open-label, proof-of-concept study in women with metastatic breast cancer, where the primary objective was to determine whether treatment with the Na+/K+ ATPase inhibitor digoxin could reduce mean CTC cluster size. - The study met its primary endpoint with a significant reduction in average cluster size between pre- and posttreatment and a similar dissolution effect in both homotypic and heterotypic clusters. - Mechanistically, transcriptome profiling of CTCs highlighted downregulation of cell–cell adhesion and cell-cycle-related genes upon treatment with digoxin, in line with its cluster-dissolution activity.  - Although clinical outcome endpoints were not assessed in this proof-of-concept study, this trial provides first-in-class evidence that supports the design of novel approaches for metastasis prevention. - Future studies will be designed for a longer treatment duration, more frequent monitoring of drug serum levels or higher dosage or using refined Na+/K+ ATPase inhibitors with stronger cluster-dissolution activity and aimed at measuring clinical endpoints related to new metastasis development. https://lnkd.in/ermwkNXg #cancer #breastcancer #metastasis #cancerresearch #oncology