Chuang, C. | bioRxiv Science

bioRxiv2026

Ulacamten: A Novel, RLC-Targeting Cardiac Myosin Inhibitor for Potential Treatment of Cardiac Hypercontractility, Including HFpEF

BackgroundCardiac myosin inhibitors (CMIs) demonstrate advantages over other guideline-directed therapy for patients with obstructive hypertrophic cardiomyopathy (oHCM). By reducing hypercontractility, CMIs abrogate excessive systolic function and improve diastolic function; diminish hypertrophy of the left ventricle (LV); and improve exercise capacity, functional class, and symptoms. Whether CMIs are therapeutic in heart failure with preserved ejection fraction (HFpEF) is of interest because a significant subset of these patients demonstrate supranormal ejection fractions and abnormal LV structure, characteristics in common with HCM, where CMIs have proved effective. ObjectivesOur goal was to characterize the mechanism of myosin inhibition for ulacamten and determine its efficacy in a rodent model of HFpEF. MethodsUlacamten was characterized using biophysical and biochemical approaches, cardiomyocytes from humans and the ZSF1 obese rat model of HFpEF, hypercontractile human-engineered heart tissues, and echocardiography in the ZSF1 rat model. ResultsUnlike the other CMIs, aficamten and mavacamten, ulacamten binds outside the S1 domain of myosin and requires the regulatory light chain domain to bind and inhibit the activity of 2-headed myosin. Ulacamten only partially inhibits the myosin ATPase activity in both myofibrillar and protein systems, but inhibition of contractility was nearly complete in cardiomyocytes. Improvement in relaxation was demonstrated in hypercontractile-engineered heart tissues, and chronic treatment of ZSF1 obese rats showed benefits in both cardiac structure and function. ConclusionsUlacamten inhibits myosin in a manner distinct from aficamten and mavacamten, potentially broadening the mechanistic properties of CMIs available for treatment of hypercontractile cardiac dysfunction. CONDENSED ABSTRACTCardiac myosin inhibitors (CMIs) abrogate excessive systolic function and improve diastolic function, diminish cardiac hypertrophy, and improve exercise capacity in humans with obstructive hypertrophic cardiomyopathy (oHCM). Supranormal ejection fraction underlies heart failure with preserved ejection fraction (HFpEF) in some patients. We describe a new CMI, ulacamten, with binding and inhibitory properties distinct from two other FDA-approved CMIs, aficamten and mavacamten. Specifically, ulacamten requires 2-headed myosin to inhibit activity, whereas aficamten and mavacamten inhibit single-headed myosin. Ulacamten inhibits contractility in primary myocytes isolated from control human and hypercontractile ZSF1 obese rat hearts, as well as engineered heart tissues created with induced pluripotent stem cell cardiomyocytes bearing an HCM mutation. Chronic treatment of ZSF1 obese rats as a preclinical model of HFpEF improves diastolic function and reduces hypertrophy and fibrosis, broadening the potential mechanistic landscape of CMIs. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/701387v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11f9cecorg.highwire.dtl.DTLVardef@776847org.highwire.dtl.DTLVardef@15f19ddorg.highwire.dtl.DTLVardef@9b20c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation

Tumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of metastasis and lymph node metastases portend worse outcomes. Through cross-species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-{gamma} and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor-draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases.

cancer biology↗