RG7741 / Roche, Pfizer - LARVOL DELTA

αGal9Ab Treatment As a Novel Therapy for Blood Cancer (ASH 2023) - "Notably, αGAL-9Ab treatment synergized with multiple CHEK1 inhibitorscurrently being tested in phase I or II clinical trials (GDC-0575, Prexasertib and PF477736) to enhance the in vitro killing of human T-ALL, B-ALL, and AML cells. In conclusion, single-agent αGAL-9Ab treatment appears to be cytotoxic against multiple acute leukemia subtypes ( ALs) and its efficacy is enhanced with CHEK1 inhibition. To validate this novel combinatorial approach for treating ALs, additional studies need to be performed to define the mechanisms of action and further pre-clinical experiments will be invaluable in determining the efficacy and safety of these therapies."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • CHEK1 • LGALS9 • MCL1

Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine (gem) in patients (pts) with refractory solid tumors (ESMO 2017) - P1; "The Chk1 inhibitor GDC-0575 can be safely combined with a standard or modified dose and schedule of gem. Hematological toxicities were frequent but manageable. Preliminary anti-tumor activity was observed in patients with a variety of refractory solid tumors treated with GDC-0575 in combination with gem 500 mg/m2."

Combination therapy • P1 data • Non Small Cell Lung Cancer • Sarcoma • Small Cell Lung Cancer • Triple Negative Breast Cancer

Novel Athero-protective Role Of Chk1-induced Senp2 S344 Phosphorylation Under Laminar Flow (ATVB-PVD-GPM 2022) - "The CHK1 specific inhibitor of GDC0575 and the depletion of CHK1 inhibited LF-induced SENP2 S344 phsophorylation and increased both p53 and ERK5 SUMOylation in ECs...The radiation reduced CHK1 expression in ECs, which may explain the different regulatory pattern under BMT or non-BMT. Taken together, these results suggest the critical role of CHK1-mediated SENP2 S344 phosphorylation on LF-induced anti-AthS effects."

Atherosclerosis • Bone Marrow Transplantation • Cardiovascular • Dyslipidemia • Transplantation • CASP3 • CDKN1A • CHEK1 • ICAM1 • SENP2

Elucidating the Structure and Cytochrome P450-mediated Mechanism for Novel Metabolites of GDC-0575 in Rats. (PubMed, Xenobiotica) - "To verify this hypothesis, we attempted to trap the intermediate I with glutathione (GSH) trapping assay and the GSH conjugate on the pyrrole ring was identified. This suggests the oxidation on the pyrrole led to reactive metabolite formation and supported this proposed mechanism."

Journal • Preclinical • Oncology • CHEK1

Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling. (PubMed, Neurotherapeutics) - "GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer's disease and highlights the therapeutic potential of Chk1 inhibitors in AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CIP2A

Combinatorial Inhibition of Galectin-9 and CHK1 Represent a Novel Treatment Strategy for T-Cell Acute Lymphoblastic Leukemia (ASH 2021) - "Given that GDC-0575 inhibits CHK1 activity, and CHK1 is a master regulator of the DNA damage response, we predict that the enhanced cytotoxicity of human T-ALL cells treated with the combination therapy results from the inability to effectively repair DNA damage induced by αGal-9Ab treatment. Our findings describe a previously unrecognized role for Gal-9 in T-ALL pathogenesis and demonstrates the cytotoxic effects αGal-9Ab treatment (including LYT-200) in preclinical models of human T-ALL."

Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • T Acute Lymphoblastic Leukemia • Transplantation • CHEK1

GDC-0575, a CHK1 Inhibitor, Impairs the Development of Colitis and Colitis-Associated Cancer by Inhibiting CCR2 Macrophage Infiltration in Mice. (PubMed, Onco Targets Ther) - "Furthermore, we report a positive correlation between CHK1 expression and CCL2/CCR2 expression in the malignant tissues of patients with CRC. Taken together, we infer that GDC-0575 impairs the development of CAC and colitis by regulating cytokine expression and inhibiting CCR2 macrophage infiltration in mice colon."

Journal • Preclinical • Colorectal Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Oncology • Solid Tumor • CCL2 • CD4 • CD8 • IL10 • IL1B • IL6 • TNFA

Gemcitabine and novel Chk1 inhibitor GDC-0575 demonstrate synergistic effect against high-grade serous ovarian cancer in 3D cell culture, PDX models and patient tumors (SGO 2020) - "Combination of gemcitabine plus GDC-0575 demonstrates synergistic tumor killing effects in vitro PDX tumors and patient tumors. Combination therapy also improves tumor killing in vivo PDX models. Further investigation into mechanisms of synergy and resistance is required."

Gemcitabine and novel Chk1 inhibitor GDC-0575 demonstrate synergistic effect against high-grade serous ovarian cancer in 3D cell culture, PDX models and patient tumors (SGO 2020) - "Combination of gemcitabine plus GDC-0575 demonstrates synergistic tumor killing effects in vitro PDX tumors and patient tumors. Combination therapy also improves tumor killing in vivo PDX models. Further investigation into mechanisms of synergy and resistance is required."

Gemcitabine and novel Chk1 inhibitor GDC-0575 demonstrate synergistic effect against high-grade serous ovarian cancer in 3D cell culture, PDX models and patient tumors (SGO 2020) - "Combination of gemcitabine plus GDC-0575 demonstrates synergistic tumor killing effects in vitro PDX tumors and patient tumors. Combination therapy also improves tumor killing in vivo PDX models. Further investigation into mechanisms of synergy and resistance is required."

Gemcitabine and novel Chk1 inhibitor GDC-0575 demonstrate synergistic effect against high-grade serous ovarian cancer in 3D cell culture, PDX models and patient tumors (SGO 2020) - "Combination of gemcitabine plus GDC-0575 demonstrates synergistic tumor killing effects in vitro PDX tumors and patient tumors. Combination therapy also improves tumor killing in vivo PDX models. Further investigation into mechanisms of synergy and resistance is required."

Enhancing abiraterone acetate efficacy in androgen receptor-positive triple negative breast cancer: Chk1 as a potential target. (PubMed, Clin Cancer Res) - "This study suggests that apocrine features can be helpful in the identification of AA-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs."

Clinical • Journal

CHK1 Inhibition in Soft-Tissue Sarcomas: Biological and Clinical Implications. (PubMed, Ann Oncol) - "Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2. We provide the first pre-clinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase 2 setting."

Clinical • Journal

Endogenous replication stress marks melanomas sensitive to CHK1 inhibitors in vivo. (PubMed, Clin Cancer Res) - "CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated to increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumours, and may be useful marker of replication stress in vivo."

Journal • Preclinical

Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. (PubMed, Ann Oncol) - P1; "Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. NCT01564251."

Clinical • Combination therapy • Journal • P1 data

Subclinical doses and choice of replication stress inducer in combination with CHK1 inhibitors for optimal tumor control and immune responses in vitro and in vivo (AACR 2019) - "We report that low dose HU increased the sensitivity of >70% of both melanoma and NSCLC cell lines to CHK1 inhibitor (GDC-0575) triggered apoptosis, with complete loss of viability found with clinically achievable doses of this combination. Similar sensitivity was observed in xenograft models of both melanoma and NSCLC. We also demonstrate that a low dose of Gemcitabine combination with CHK1 inhibitor results in complete loss of proliferative potential in normal tissue, whereas normal tissue retaining proliferative potential after treatment with even high doses of hydroxyurea in combination with CHK1 inhibitor."

Combination therapy • Preclinical