GRN-300 / Arrien, Greenfire Bio - LARVOL DELTA

Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer. (PubMed, Res Sq) - "In ovarian cancer xenograft models, GRN-300 plus chloroquine markedly suppressed tumor growth and significantly prolonged survival compared with either monotherapy. Together, these findings identify SIK2/3 as key regulators of ER stress-induced ER-phagy and reveal a targetable stress-adaptation pathway that can be exploited therapeutically in ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • ATF4 • ERN1

Targeting SIK2 with GRN-300 Potentiates Paclitaxel Efficacy in Triple-Negative Breast Cancer. (PubMed, Cancers (Basel)) - "Together, these findings establish GRN-300 as a promising therapeutic agent that enhances paclitaxel efficacy through complementary disruption of mitotic regulatory pathways, providing strong preclinical rationale for clinical development in TNBC."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC27 • CDK1 • ER • HER-2 • PGR • PLK1

GRN-300 restores PARP inhibitor sensitivity through inhibition of the HDAC-MEF2A-RAD51 pathway in BRCA2-revertant ovarian cancer (AACR 2026) - "GRN-300 markedly reduced the IC₅₀ of olaparib in both PARP-sensitive PEO1 cells (1.98 to 0.64 µM) and resistant BRCA2-revertant PEO1-C4-2 (6.87 to 0.92 µM) and PEO4 (3.47 to 1.17 µM) ovarian cancer cells, restoring responsiveness. ChIP-qPCR revealed reduced MEF2A binding to regulatory regions of DNA repair genes, including RAD51 and RAD50, thereby suppressing DSB end resection and strand invasion mediated by the MRN complex. In summary, GRN-300 restores PARP inhibitor sensitivity in BRCA2-revertant ovarian cancer through inhibition of the HDAC-MEF2-RAD51 pathway, providing a promising therapeutic strategy to overcome PARP resistance."

Oncology • Ovarian Cancer • Solid Tumor • AMPK • BRCA1 • BRCA2 • CASP3 • CASP7 • HDAC4 • HRD • RAD50 • RAD51

Dual inhibition of SIK2/3 induces ER Stress and ER-phagy, enhancing the cytotoxicity of autophagy blockade in ovarian cancer (AACR 2026) - "In three ovarian cancer xenograft models (OVCAR8, OC316, and SKOv3), GRN-300 plus CQ markedly suppressed tumor growth, increased apoptotic markers, and significantly prolonged survival compared to either monotherapy. These findings reveal a previously unrecognized role of SIK2/3 inhibition in driving ER stress and CCPG1-mediated ER-phagy and provide strong rationale for combining GRN-300 with autophagy inhibition as a promising therapeutic strategy for ovarian cancer."

Oncology • Ovarian Cancer • Solid Tumor • ATF4 • ATF6 • ERN1

Identification of pharmacodynamic biomarkers in PBMCs and cancer cells for SIK2 kinase inhibitor therapy (AACR 2024) - P1 | "SIK2 inhibitors synergistically enhance sensitivity of ovarian and breast cancer cells to paclitaxel, carboplatin and PARP inhibitors. Five genes - ID1, ID2, ID3, ID4 and TGFBI - are down-regulated in response to GRN-300 treatment in more than 10 of 13 cell lines. The decrease in HDAC4/5/7 phosphorylation, and alterations in mRNA markers we discovered could serve as PD biomarkers for clinical trials to evaluate the effects of SIK2 inhibitors and provide insights in the mechanisms of drug action."

Biomarker • PK/PD data • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Ovarian Cancer • Solid Tumor • AMPK • DDIT4 • HDAC4 • IL6 • MS4A6A • mTOR • RNASE1 • STK11 • TGFBI

A Review of SIK2 in Ovarian Cancer: Function and Emerging Targeted Therapies. (PubMed, Onco Targets Ther) - "Unlike previous reviews that broadly cover the SIK family or general ovarian cancer metabolism, this review provides a SIK2-centered perspective, comprehensively synthesizing its multifaceted oncogenic roles and systematically evaluating emerging targeted therapies-including ATP-competitive inhibitors (ARN-3261, MRIA9), a protein degrader (SIC-19), and a novel hydrogel delivery system (Gel Nap-S+HG). Despite these promising developments, it is important to note that most SIK2-targeted agents are still in preclinical stages, and several critical hurdles remain to be addressed before clinical translation-including off-target toxicity, limited selectivity, and the lack of validated predictive biomarkers for patient stratification. By integrating current mechanistic insights with an up-to-date evaluation of emerging therapies, this review provides a foundational framework for guiding future research and supporting the clinical development of SIK2-targeted strategies in..."

Journal • Review • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

GRN300-001: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1 | N=73 | Suspended | Sponsor: Green3Bio, Inc. | Active, not recruiting ➔ Suspended

Combination therapy • Trial suspension • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

GRN300-001: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1 | N=73 | Active, not recruiting | Sponsor: Green3Bio, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

GRN300-001: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1 | N=73 | Recruiting | Sponsor: Green3Bio, Inc. | Trial completion date: Mar 2023 ➔ Mar 2025 | Trial primary completion date: Dec 2022 ➔ Dec 2024

Combination therapy • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

GRN300–001: Phase 1/1B evaluation of the safety, pharmacokinetics, and efficacy of GRN-300, a salt-inducible kinase inhibitor, alone and in combination with paclitaxel, in recurrent ovarian, primary peritoneal, and fallopian tube cancers. (ASCO 2022) - P1 | "The first 3 dose groups (100, 200, and 300 mg BID of GRN-300) have been completed without DLT and preliminary PK analysis indicate dose proportionality. Enrollment to dose group 4 (400 mg BID) began in February 2022."

Clinical • Combination therapy • P1 data • PK/PD data • Fallopian Tube Cancer • Oncology • Ovarian Cancer

Green3Bio Announces Publication of Pre-Clinical Data Demonstrating SIK2 Inhibition (including GRN-300) Enhances PARP Inhibitor Activity Synergistically in Ovarian and Triple Negative Breast Cancers. (PRNewswire) - "Green3Bio Announces Publication of Pre-Clinical Data Demonstrating SIK2 Inhibition (including GRN-300) Enhances PARP Inhibitor Activity Synergistically in Ovarian and Triple Negative Breast Cancers. The major findings from the preclinical research study include: 1. GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity; 2. The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300; 3. GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis; 4. Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC."

Preclinical • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers. (PubMed, J Clin Invest) - "We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • DRD • FANCD2 • HDAC4 • MEF2D • XRCC4

Greenfire Bio to update progress on Phase 1 Clinical Trial for SIK2/SIK3 inhibitor, GRN-300, in ovarian cancer at the ASCO Annual Meeting 2022 (PRNewswire) - P1 | N=64 | NCT04711161 | Sponsor: Green3Bio | "Greenfire Bio...will present an update on the ongoing first-in-human clinical trial of GRN-300 at the upcoming ASCO 2022 Annual Meeting. GRN-300 is a first-in-class, orally bioavailable novel small molecule inhibitor of the Salt Inducible Kinases 2 and 3 (SIK2/SIK3) that is highly expressed in ovarian cancer and has been identified to play a pivotal role in several other cancers. The transition of this emerging biologic pathway and a novel agent into the clinic marks a successful step in the progress of the GRN-300 program."

P1 data • Gynecologic Cancers • Oncology • Solid Tumor

A Novel Salt Inducible Kinase 2 Inhibitor, ARN-3261, Sensitizes Ovarian Cancer Cell Lines and Xenografts to Carboplatin. (PubMed, Cancers (Basel)) - "Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor

First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1; N=64; Recruiting; Sponsor: Green3Bio, Inc.

Clinical • Combination therapy • New P1 trial • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor