SRA737 / Sareum - LARVOL DELTA

In vivo screening reveals therapeutic vulnerabilities in a patient-derived xenograft established from an intraosseous TFCP2-rearranged rhabdomyosarcoma (AACR 2025) - "PDX174 was derived prior to ALKi treatment (lorlatinib) and PDX199 from the same patient following disease progression after 16 months of lorlatinib therapy...In addition, while CDK4/6 inhibitor, palbociclib, and CHK1 inhibitor, SRA737, induced moderate inhibition of tumor growth, drug resistance quickly followed within 2 weeks. Global kinome analysis indicated a significant increase in the mitogen- and stress-activated kinase 1 (MSK1) in AZD5153-resistant tumors compared to the vehicle group, revealing a potential therapeutic vulnerability in the BETi-resistant tumors. IORMS models such as PDX174/PDX199 are crucial for revealing actionable molecular signatures before and after targeted therapy and will increase our mechanistic understanding of tumor adaptive responses and aid in designing therapies that mitigate the emergence of therapeutic resistance."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ALK • FUS • TERT • TFCP2

Sareum Acquires Licence for SRA737 (London stock exchange) - "Sareum Holdings plc...is pleased to announce that it has acquired the licence for SRA737 following the programme's return from a US-based biopharma company.... Sareum has now acquired the licence and renegotiated the economic terms under which it will receive a net 63.5% of all future revenues, compared to 27.5% under the former agreement. The remaining interest is divided between CPF and Cancer Research Technology, the commercialisation arm of Cancer Research UK."

Commercial • Oncology

Sareum Holdings Refocuses Strategy After SRA737 Licensing Termination (Business Insider) - "Sareum Holdings plc has announced the termination of the licensing agreement for its cancer drug candidate SRA737 by a U.S.-based biopharma company, effective in March 2025. Despite the setback, Sareum remains committed to advancing its pipeline of TYK2/JAK1 inhibitors, particularly focusing on SDC-1801, which is poised for Phase 2 development, thereby signaling a shift in strategic focus towards its in-house projects."

Commercial • Pipeline update • Solid Tumor

ATR Inhibitor Elimusertib Suppresses Drug Persister Clones in TP53-Mutated Acute Myeloid Leukemia Via CGAS-Sting-Mediated Cell Death (ASH 2024) - "Among these, the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor elimusertib (BAY1895344) effectively inhibited TP53 mut AML DTPCs at low doses, similar to known inhibitors the CHK1 inhibitor (SRA737) and the Wee1 inhibitor (Adavosertib)...Furthermore, the triple combination treatment of cytarabine, idarubicin, and elimusertib effectively suppressed DTPC formation in TP53 mut AML cell lines...This consequently results in cGAS-STING-mediated cell death following irreparable DNA replication stress accompanied by p53 dysfunction. Our findings provide a basis for developing optimized treatment strategies for patients with TP53-mutant AML using the ATR inhibitor elimusertib."

Acute Myelogenous Leukemia • Ataxia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Oncology • Primary Immunodeficiency • CDC25C • CDK1 • CDKN1A • CXCL10 • GNRP • IFI27 • IFIT1 • RSAD2 • SIGLEC1 • STAT1 • STING • TP53

Pharmacoinformatics-based prediction of Checkpoint kinase-1 inhibitors from Momordica charantia Linn. for cancer. (PubMed, Comput Biol Chem) - "Among 86 compounds identified from M. charantia L., five molecules such as α-spinasterol (-9.7 kcal × mol-1), stigmasterol (-9.6 kcal × mol-1), stigmasta-7,22,25-trienol (-9.5 kcal × mol-1), campesterol (-9.5 kcal × mol-1), and stigmasta-7,25-dien-3beta-ol (-9.5 kcal × mol-1) and standard drug CCT245737 (-8.3 kcal × mol-1) displayed highest binding affinity with Chk-1...The estimation of binding free-energy derived from molecular docking was fully recognized by the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) produced from the MD simulation paths. Altogether, these five compounds may serve as effective inhibitors of Chk-1, thereby could be used to develop new medications for cancer treatment."

Journal • Oncology • CHEK1

Characterizing functional DNA damage and response caused by the combination of CHK1 and WEE1 inhibitors in ovarian and breast cancer models. (PubMed, BJC Rep) - "The combination of the CHK1 inhibitor SRA737 and WEE1 inhibitor adavosertib causes growth inhibition in-vitro and in-vivo, but differential functional inhibition of DDR in the models studied."

Journal • Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer. (PubMed, iScience) - "SRA737 monotherapy in vivo prolonged survival in CCNE1 amp models, suggesting a potential biomarker for CHK1i therapy. Combination SRA737 and PARPi therapy increased tumor regression in both PARPi-resistant and CCNE1 amp patient-derived xenograft models, warranting further study in these HGSOC subgroups."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • CCNE1 • HRD

Cell context-dependent role of KDM5D in ATR and CHK1 inhibitor sensitivity in prostate cancer (AACR 2024) - "Loss of KDM5D expression was associated with reduced cell proliferation and resistance to the CHK1 inhibitor SRA737 in castration-resistant (CRPC) and neuroendocrine (NEPC) prostate cancer cell lines...This study may uncover novel biomarkers for ATR and CHK1 inhibitors that are currently in clinical trials for various cancers. KDM5D may be used to stratify prostate cancer patients receiving these highly potent anticancer agents."

Late-breaking abstract • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • KDM5D

Targeting Replication Stress Using a CHK1 Inhibitor Combination Promotes Anti-tumour Immune Responses that is Suppressed by Tumour-associated Myeloid cells. (EACR-AACR 2024) - "Material and Methods Syngeneic mouse melanoma and ovarian cancer models were treated in vivo with the combination of CHK1i SRA737 and low dose hydroxyurea. Reducing tumour associated myeloid number or activity was associated with enhanced anti-tumour immune responses. This work suggests that the myeloid component of tumours may significantly alter treatment responses by suppressing anti-tumour immune activity."

Melanoma • Oncology • Ovarian Cancer • Solid Tumor • CD8 • CHEK1 • CSF1R

Development and commercialisation licence SRA737 (Sareum Press Release) - "Sareum Holdings plc...today announces that the Company's co-development partner, the CRT Pioneer Fund ('CPF'), has entered into a development and commercialisation licence agreement for SRA737 (the 'Licensing Agreement') with a private biopharma company based in the United States (the 'Licensee Company')....Under the terms of the Licensing Agreement, an immediate upfront payment of US$0.5 million is due to CPF. An additional fee made up of up to US$1.0 million cash and 500,000 shares in the Licensee Company (the 'Consideration Shares') may be payable upon the sooner of 12 months following the signing of the Licensing Agreement, or the event of the Licensee Company achieving certain commercial and material financing objectives. A further announcement regarding any future income, including any Consideration Shares which may be issued, will be made at the appropriate time."

Licensing / partnership • Oncology • Solid Tumor

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer (Oncogene, Nature) - "Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC."

Preclinical • Castration-Resistant Prostate Cancer • Neuroendocrine Tumor

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer (Oncogene, Nature) - "Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC."

Preclinical • Castration-Resistant Prostate Cancer • Neuroendocrine Tumor

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer. (PubMed, Oncogene) - "Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC."

Journal • Synthetic lethality • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • WEE1

Investigations of the novel checkpoint kinase 1 inhibitor SRA737 in non-small cell lung cancer and colorectal cancer cells of differing tumour protein 53 gene status. (PubMed, Explor Target Antitumor Ther) - "Also, greater anti-proliferative and cell killing effects were noted in the TP53 MUT cells than in the TP53 WT cells. This study's data suggests that P53 status/functioning is a key factor in determining the sensitivity of NSCLC and CRC cancer cells towards CHK1 inhibition, even in circumstances conducive to high replicative stress."

Journal • Ataxia • Colorectal Cancer • Gastrointestinal Cancer • Immunology • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Primary Immunodeficiency • Solid Tumor • CHEK1 • CHEK2

Cisplatin and Procaterol Combination in Gastric Cancer? Targeting Checkpoint Kinase 1 for Cancer Drug Discovery and Repurposing by an Integrated Computational and Experimental Approach. (PubMed, OMICS) - "An e-pharmacophore model was developed based on the three-dimensional crystal structure of the CHK1 protein in complex with CCT245737. Thus, we propose the combined application of cisplatin and procaterol as a novel potential therapeutic strategy against human gastric cancer. The findings also highlight the relevance of CHK1 kinase as a drug target for enhancing the sensitivity of cytotoxic agents in cancer."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CHEK1

INHIBITION OF THE DNA DAMAGE RESPONSE: A POSSIBLE NEW ROUTE IN ACUTE MYELOBLASTIC LEUKEMIA TREATMENT (EHA 2023) - "CCT245737 and niraparib reduced cell proliferation and viability in a dose-, time- and cell-line-dependent manner. KG-1 cells (IC 50 of 47 μM at 48 hours) were the most sensitive to CHK1 inhibition while LAMA-84 cells (IC 50 of 78 μM at 48 hours) were the most resistant. The most sensitive cell line to niraparib was NB-4 (IC 50 of 20 μM at 48 hours) and the most resistant was KG-1 (IC 50 of 68 μM at 48 hours)."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5

Drug-tolerant persister cells arise and mediate resistance to targeted CHK1 inhibition (EACR 2023) - "Herein, we sought to investigate the emergence and progression of DTPs in response to treatment with the clinical candidate SRA737; a small molecule inhibitor of checkpoint kinase 1 (CHK1) that targets the DNA damage response (DDR) pathway.Material and MethodsSK-N-AS cells were exposed to lethal concentrations of SRA737 for 7 and 50 days to generate DTP and drug-tolerant expanded persister (DTEP) populations, respectively...Inhibition of the H3K27 methyltransferase EZH2 using tazemetostat inhibits DTP-to-DTEP transition but fails to abrogate DTP prevalence or DTEP survival, confirming the requirement of epigenetic plasticity for persister cell progression...Comparison to dose-escalated cells reveals a specific enrichment of genes associated with JAK-STAT signalling in persister-derived populations.ConclusionWe have characterised the persister cell response within a novel and clinically relevant therapeutic context and identified EZH2 activity and JAK-STAT signalling as..."

Oncology • CHEK2

A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. (PubMed, Br J Cancer) - P1/2 | "SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy."

Journal • Metastases • P1/2 data • Gastrointestinal Disorder • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia

"Udai, Does SRA 737 have a future as a combination therapy (in your opinion)?" (@triumphisbest)

Combination therapy

Wee1 inhibition and its synthetic lethal combination with Chk1 inhibition in mouse model of neuroendocrine prostate cancer (AACR 2023) - "Using an autochthonous adenocarcinoma mouse prostate (TRAMP) model that gives rise to NEPC tumors, we assessed the efficacy of AZD1775 and a highly selective Chk1 inhibitor SRA737 as single agents and in combination on the progression, survival, and metastatic spread of NEPC tumors in vivo. Mechanistically, the combination of Chk1 and Wee1 inhibitors synergized to reduce the inhibitory phosphorylation of CDK1 at Y15 and Cdc25c at S216, resulting in enhanced activation of CDK1/cyclin B complex, abrogation of G2/M checkpoint, and consequent premature mitotic entry, which ultimately led to mitotic catastrophe and apoptosis. Our findings provide promising preclinical evidence supporting the therapeutic values of Wee1 and Chk1 inhibitors as single agents and in combination for the treatment of NEPC."

Preclinical • Synthetic lethality • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • CDC25C • CDK1 • GNRP • WEE1

Discovery of a novel and oral CHK1 inhibitor for the treatment of solid tumors (AACR 2023) - "Others are related to their limited clinical efficacy, such as SRA737 which selectively inhibits CHK1 but not CHK2. Prexasertib (LY2606368), one of the few agents to undergo clinical trials, specifically inhibits both CHK1 and CHK2, displaying obvious therapeutic effects but also raising inevitable target-associated drug toxicities and a potential compliance issue due to intravenous administration...Moreover, the combination of XS-02 and olaparib, a PARP inhibitor, accelerated tumor regression, which synergy was confirmed in a patient-derived tumor xenograft animal model of acquired resistance to olaparib, without significant body weight changes...These results support the agent as a clinical candidate for the treatment of solid tumors. An Investigational New Drug application is planned for 2023."

Oncology • Solid Tumor

"@LCleaders @LungCancer_Bio @UpstageLungCanc @BigCodsy @LungCancer_Can @LungCancerConne @lungcancerpall @lgreco_ny @LCAM_org @IrishLungCancer @paulamchadwick @fsglmt @lung_ca_screen @LungPolicy @LungCAN @LC_Initiative_ @sra737PRTeam @VirginiaMByrne @SteligaMD @targtlungcancer" (@YLeyfman)

Lung Cancer • Oncology • Solid Tumor

"@fsglmt @lung_ca_screen @LungPolicy @LungCAN @LC_Initiative_ @sra737PRTeam @VirginiaMByrne @SteligaMD @targtlungcancer @DrewMoghanaki @lungcancer101 @IFCTlung @DavidCookeMD @Tasmanian_LCR @DrSteveMartin @HosseinBorghaei @R2SurviveCancer @BenjaminBesseMD @heidi_onda @bensolomon1" (@YLeyfman)

Lung Cancer • Oncology • Solid Tumor

"Did you not carry out many tests including SRA737 and found it to be of good efficacy why was it not carried on" (@jilita)

Clinical

"SRA737" (@jilita)