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ORIN1001

ORIN1001 is a novel and selective IRE1α RNAse inhibitor

  • ORIN1001 is an oral agent and is poised for Phase 2 clinical trials for the treatment of advanced solid tumors and metastatic breast cancer. 

    • Phase 1 dose escalation is complete as a monotherapy and in combination with chemotherapy. 

    • A Phase 2 trial is poised to start.​

    • Phase 1 oncology trials were conducted in the US and China.

  • A Phase 1b trial was conducted in the US in IPF patients.

  • IRE1 is thought to promote cell survival during conditions of cellular stress (for example, starvation, hypoxia, cancer and chemotherapy).  In most healthy cells, the IRE1 pathway is not active until these stress conditions occur.

ORIN1001 is a first-in-class drug that provides an innovative approach to kill cancer cells by decreasing survival of cancer cells.  ORIN1001 also decreases fibrosis in Idiopathic Pulmonary Fibrosis. 

 

Our data indicate that ORIN1001 may be effective alone or in combination with standard of care, thereby facilitating the action of these other therapies, allowing use in expanded patient populations.

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In preclinical models and in patient-derived xenografts, ORIN1001 has been shown to inhibit IRE1 activity and anti-tumor growth across multiple tumor types including breast, prostate, pancreatic, lung, liver, colon, esophageal and other solid tumors.  ORIN1001 is an anti-fibrotic agent that shows marked efficacy in preclinical models of IPF.

ORIN1001 is a first-in-class small molecule targeting a novel enzyme with a unique mode of inhibition that selectively blocks the Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum. 

Select Literature with ORIN1001:

  • Leukocyte- intrinsic ER stress responses contribute to chemotherapy- induced peripheral neuropathy. Sci. Transl. Med. 17, eady5288 (2025)

  • Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors. Science 2023, 381 (6662)

  • Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia. Carcinogenesis 2020 9 11

  • The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells. Cancer Lett 2020 490,76-88

  • Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo   Cancer Letters 2020, 494, 73-83

  • Pharmacological targeting of the unfolded protein​ response for disease intervention.  Nature.  2019 15, 764-775

  • Inhibition of IRE1α RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1β    Cell Death & Disease 2019, 10(9), 622

  • IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling   Nat. Comm. 2019, 10(1), 323

  • Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy  Nat. Comm. 2018, 9(1), 1-14

  • Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer” JCI  2018, 128(4), 1283-1299

  • Structure and mechanism of action of the hydroxy aryl aldehyde class of IRE1 endoribonuclease inhibitors Nat. Comm. 2014, 5, 4202

  • Disruption of microRNA Biogenesis Confers Resistance to ER Stress-Induced Cell Death Upstream of the Mitochondrion PLoS ONE 2013, 8(8), e73870

  • Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma Blood, 2012, 119(24), 5772-5781

  • Autophagy and the unfolded protein response promote profibrotic effects of TGF-b1 in human lung fibroblasts, Ghavami et al., Am J Physiol Lung Cell Mol Physio  2018

  • Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein, JCI Insight 2018; 3(16)

  • IRE1α–XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science 2019, 365 6499.

 

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