Z-Lock: Targeting Z-RNA for Cancer Immunotherapy

At Dynoma Biosciences, we are developing a new pharmaceutical approach to cancer immunotherapy based on manipulating the structural state of cellular RNA. Our lead research program, Z-Lock, is focused on developing pharmaceutical molecules designed to stabilize the Z-conformation of double-stranded RNA (Z-RNA) and harness its potential as an endogenous trigger of innate immunity and cancer cell death.

Z-RNA is a transient, left-handed conformation of double-stranded RNA (dsRNA) that differs structurally from the more common right-handed A-form RNA duplex. Although Z-RNA can form naturally within cells, its formation is dynamic and normally short-lived. Importantly, Z-RNA can be recognized by Z-DNA-binding protein 1 (ZBP1), an innate immune sensor capable of initiating powerful inflammatory and cell-death signaling. Activation of ZBP1 can engage interconnected pathways of pyroptosis, apoptosis, and necroptosis—collectively described as PANoptosis—providing an intriguing opportunity to simultaneously promote tumor cell elimination and stimulate anti-tumor immunity.

Z-Lock is being developed to pharmacologically stabilize Z-form dsRNA, increasing the persistence of this otherwise transient RNA conformation and thereby promoting its recognition by ZBP1. Our therapeutic hypothesis is that enhancing Z-RNA–ZBP1 signaling in cancer cells could trigger PANoptotic cell death while simultaneously generating inflammatory signals capable of enhancing anti-cancer immune responses.

Z-Lock → Z-RNA stabilization → ZBP1 activation → PANoptosis → cancer cell death + anti-cancer immune response

This strategy represents a distinct approach to pharmaceutical epitranscriptomics. Rather than targeting a conventional oncogenic protein, Z-Lock is designed to manipulate the structural state of RNA itself. By pharmacologically controlling RNA conformation, we aim to transform endogenous RNA into a therapeutic signal capable of activating innate immune surveillance from within the cancer cell.

At Dynoma Biosciences, we use state-of-the-art discovery and development platforms to advance the Z-Lock program. Our approach integrates genome- and transcriptome-scale analysis of alternative nucleic-acid conformations with molecular screening and characterization to identify, develop, and optimize candidate molecules capable of modulating Z-RNA dynamics. These capabilities are intended to help us understand where and when alternative RNA structures form, determine how their stabilization affects cellular signaling, and systematically evaluate candidate Z-Lock molecules for their ability to engage the desired Z-RNA–ZBP1 pathway.

This strategy represents a distinct approach to pharmaceutical epitranscriptomics. Rather than targeting a conventional oncogenic protein, Z-Lock is designed to manipulate the structural state of RNA itself. By pharmacologically controlling RNA conformation, we aim to transform endogenous RNA into a therapeutic signal capable of activating innate immune surveillance from within the cancer cell.

At Dynoma Biosciences, we use state-of-the-art discovery and development platforms to advance the Z-Lock program. Our approach integrates genome- and transcriptome-scale analysis of alternative nucleic-acid conformations with molecular screening and characterization to identify, develop, and optimize candidate molecules capable of modulating Z-RNA dynamics. These capabilities are intended to help us understand where and when alternative RNA structures form, determine how their stabilization affects cellular signaling, and systematically evaluate candidate Z-Lock molecules for their ability to engage the desired Z-RNA–ZBP1 pathway.The potential value of this approach extends beyond direct cancer cell killing. By activating an endogenous innate immune pathway within tumors, Z-Lock could potentially help convert immunologically silent or resistant cancer cells into inflammatory targets that are more readily recognized by the immune system. This creates opportunities to investigate Z-Lock both as a stand-alone therapeutic strategy and in combination with existing cancer immunotherapies, including immune-checkpoint inhibitors.

Through Z-Lock, Dynoma Biosciences is exploring a new therapeutic paradigm in which RNA conformation itself becomes a druggable feature of cancer biology. Our goal is to establish a new class of pharmaceutical molecules that manipulate alternative RNA structures to activate innate immunity, induce cancer cell death, and ultimately expand the possibilities for precision cancer immunotherapy.