simurosertib (TAK-931) / Takeda, ZAI Lab - LARVOL DELTA

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation. (PubMed, Signal Transduct Target Ther) - "CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation."

Journal • Eye Cancer • Lung Adenocarcinoma • Oncology • Prostate Cancer • Retinal Disorders • Retinoblastoma • Solid Tumor • CDC7 • RB1 • TP53

Effect of CDC7 inhibition and MYC degradation on neuroendocrine transformation in the lung and prostate cancer. (ASCO 2024) - "Importantly, TP53/RB1-inactivation induced sensitivity to the CDC7 inhibitor simurosertib, unraveling a therapeutic vulnerability in tumors at high risk of NE transformation... In sum, CDC7 inhibition may suppress, or at least dramatically delay NE transformation in patients with lung and prostate adenocarcinomas at high risk of transformation, by inducing MYC proteasomal degradation. The clinical availability of CDC7 inhibitors, currently in phase II clinical trials after demonstrating tolerability and preliminary efficacy, will allow rapid translation of these results into the clinics."

Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • CDC7 • EGFR • RB1 • TP53

CDC7 is a targetable regulator of advanced prostate cancer (AACR 2024) - "TAK-931 treated prostate cancer cell lines also showed an abnormal cell cycle profile, indicating that inhibiting CDC7 in aggressive prostate cancer could contribute to replication stress and promote apoptosis. Overall, this study demonstrates that CDC7 is a targetable protein that regulates advanced and aggressive prostate cancer growth."

Metastases • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • Wilms Tumor • CDC7

CDC7 inhibition prevents neuroendocrine transformation in the lung and prostate through MYC degradation (AACR 2024) - "Importantly, TP53/RB1-inactivation induced sensitivity to the CDC7 inhibitor simurosertib, unraveling a therapeutic vulnerability in tumors at high risk of NE transformation...In sum, CDC7 inhibition may suppress, or at least dramatically delay NE transformation in patients with lung and prostate adenocarcinomas at high risk of transformation, by inducing MYC proteasomal degradation. The clinical availability of CDC7 inhibitors, currently in phase II clinical trials after demonstrating tolerability and preliminary efficacy, will allow rapid translation of these results into the clinics."

Lung Adenocarcinoma • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • CDC7 • EGFR • RB1 • TP53

CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade. (PubMed, Nat Commun) - "Finally, the combination of TAK-931 and immune checkpoint inhibitors profoundly enhance antiproliferative activities. These findings suggest that TAK-931 has therapeutic antitumor properties and improved clinical benefits in combination with conventional immunotherapy."

Checkpoint block • Checkpoint inhibition • IO biomarker • Journal • Oncology • CDC7

HARNESSING EWING SARCOMA'S REPLICATION STRESS BY TARGETING DDK AND WEE1 IN COMBINATION (CTOS 2023) - "Mice were treated with either no therapy (vehicle control – 5 mice), MK1775 (Wee1 inhibitor; 50 mg/kg PO daily Days 1-5) + TAK-931 (DDK inhibitor; 60 mg/kg PO daily Days 1-3) (DDKi + WEE1i - 10 mice), Trabectedin (0.15 mg/kg IV or IO weekly x 3 weeks) (10 mice), Irinotecan (15 mg/kg IV weekly) + Temozolomide (40 mg/kg IP weekly) (standard relapse comparator - 10 mice), Irinotecan + MK1775 (10 mice), Cyclophosphamide (40mg/kg IV) + Doxorubicin (3.3mg/kg IV) + Vincristine (0.5mg/kg IV) given on Day 1 once on day 1 of week 1 (standard up-front regimen – 10 mice). The novel combination of two orally bioavailable inhibitors of DDK and WEE1 already separately in single-agent study in human patients, TAK-931 and MK1775, plus irinotecan may prove to be a promising combination to treat patients with Ewing sarcoma based on our preliminary data. To our knowledge, the combination of DDK and Wee1 inhibition has not been tested in humans to date but would be a logical next step."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CDC7

CDC7 inhibition constrains lineage plasticity and prevents resistance and neuroendocrine transformation in the lung and prostate (ESMO 2023) - "Simurosertib, a CDC7 inhibitor in phase II trials, dramatically sensitized an array of chemotherapy-naïve and -resistant SCC PDXs to chemotherapeutic agents used in the first- and second-line settings for these tumors, respectively, without toxicity issues at the concentrations used...Conclusions CDC7 inhibition prevents NE transformation in lung and prostate AD, and exquisitely sensitizes NE-transformed or de novo SCCs to chemotherapy. The availability of CDC7 inhibitors currently under clinical testing will allow immediate translation of these results in two settings with extremely limited and rather ineffective therapeutic options available."

Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • CDC7 • EGFR • RB1 • TP53

Minichromosome maintenance proteins in lung adenocarcinoma: clinical significance and therapeutic targets. (PubMed, FEBS Open Bio) - "Simurosertib (TAK-931) significantly suppressed the proliferation of LUAD cells by inhibiting CDC7-mediated MCM2 phosphorylation...Moreover, analysis of the epigenetic regulation of MCM2 showed that miR-139-3p, miR-378a-5p, and miR-2110 modulated MCM2 expression in LUAD cells. In patients with LUAD, understanding the role of these miRNAs may improve prognoses."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDC7 • MCM2 • MCM4 • MCM5 • MCM7 • MIR139 • MIR378A

Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Inhibitor, in Patients with Advanced Solid Tumors: A Phase I First-in-Human Study. (PubMed, Cancer Res Commun) - P1 | "The recommend phase II dose was determined to be TAK-931 50 mg administered once daily on days 1-14 of each 21-day cycle. A phase II study is ongoing to confirm the safety, tolerability, and antitumor activity of TAK-931 in patients with metastatic solid tumors."

Journal • Metastases • P1 data • PK/PD data • Febrile Neutropenia • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • CDC7

A phase 1 open-label study to assess the relative bioavailability of TAK-931 tablets in reference to powder-in-capsule in patients with advanced solid tumors. (PubMed, Invest New Drugs) - P1 | "(Trial registration number ClinicalTrials.gov NCT03708211. Registration date October 12, 2018)."

Journal • P1 data • Oncology • Solid Tumor • CDC7

WEE1 inhibition augments CDC7 (DDK) inhibitor-induced cell death in Ewing sarcoma by forcing premature mitotic entry and mitotic catastrophe. (PubMed, Cancer Res Commun) - "This is the first study to display the potential of utilizing the combined inhibition of DDK and WEE1 for the treatment of cancer. We believe this will offer a potential therapeutic strategy for the treatment of Ewing sarcoma as well as other tumor types that display sensitivity to DDK inhibitors."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CDC7 • CDK1

CDC7 inhibitor-induced replication stress generates inflamed aneuploid cells to sensitize immune checkpoint inhibitors (AACR 2022) - "These preclinical findings suggest the therapeutic potential of TAK-931 in antitumor efficacy and immunity, which may improve clinical benefit of the currently-used immunotherapy by combination treatment."

Checkpoint inhibition • Oncology • CD8 • CDC7 • PTPRC

Zai Lab Announces Financial Results and Corporate Updates for Twelve Months Ended December 31, 2021 (GlobeNewswire) - "Anticipated 2022 Zai Milestone: Simurosertib: Initiate a Phase 2 biomarker-driven proof-of-concept study in the second quarter of 2022; ZL-1201: Determine a recommended Phase 2 dose in the ongoing Phase 1 trial in mid-2022; Present preclinical data of ZL-1201 in combination with standard of care therapeutic antibodies in hematologic and solid tumor models at the 2022 AACR annual meeting; ZL-1211: Present preclinical data of ZL-1211 (Claudin18.2), ZL-2201 (DNA-PK), and ZL-1218 (CCR8) at the 2022 AACR annual meeting."

Clinical • New P2 trial • Preclinical • Hematological Malignancies • Oncology • Solid Tumor

Assessment of Effects of Investigational TAK-931, an Oral Cell Division Cycle 7 Kinase Inhibitor on the QTc Intervals in Patients With Advanced Solid Tumors. (PubMed, Clin Pharmacol Drug Dev) - "At the geometric mean maximum TAK-931 plasma concentrations after administration of 50 mg, an HR change of 3.40 beats per minute (90%CI, 1.86-4.80) was predicted. Change in QTcF of -3.41 milliseconds (90%CI, -5.77 to -1.17) and QTcP of -2.02 milliseconds (90%CI, -4.15 to 0.0679) were estimated, indicating there was no effect of TAK-931 on the QT intervals at a recommended phase 2 dose of 50 mg once daily for 14 days in a 21-day cycle."

Journal • Oncology • Solid Tumor • CDC7

Stemness Signature Predicts Outcomes and Identifies Candidates for Targeted Therapy in Diffuse Large B-Cell Lymphoma (ASH 2021) - "CDC7 inhibitors involving in dequalinium chloride which was approved by Food and Drug Administration (FDA) for anti-microbial and simurosertib which in a phase I clinical trial for multiple solid tumors show antitumor in DLBCL cell line of SU-DHL-2 and SU-DHL-10... In a word, the study integrated DLBCL stemness, clinical characteristics and immunophenotyping, providing an idea of targeting for cold tumors of DLBCL, and also verified the efficacy of inhibitors of key gene of stemness CDC7 in DLBCL. It is significant to develop novel therapeutic targets for diffuse large B cell lymphoma. Figure Legends: Figure (A-B) An overview of the association between known clinical and molecular features (IPI, Hams, gender, and stage) and stemness index in DLBCL cohort."

Biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Zai Lab Announces Third Quarter 2021 Financial Results and Corporate Updates (GlobeNewswire) - "[For Tebotelimab] Provide an update regarding ongoing studies and plans for the next stage of development; Present preclinical data supporting combination of BLU-945 and BLU-701 in EGFR-driven NSCLC at a medical conference; Initiate Phase 1 trial of BLU-701 in EGFR-driven NSCLC in the fourth quarter of 2021; [for ZL-1201] Determine a recommended Phase 2 dose in the ongoing Phase 1 trial; [For Simurosertib] Initiate a Phase 2 biomarker-driven proof-of-concept study."

New P2 trial • Preclinical • Trial status • Lung Cancer • Non Small Cell Lung Cancer

The role of DDK and Treslin-MTBP in coordinating replication licensing and pre-initiation complex formation. (PubMed, Open Biol) - "We also show that DDK activity cooperates with CDK activity to drive the interaction of Treslin-MTBP with TopBP1 which is a regulated crucial step in pre-initiation complex formation. These results suggest how DDK works together with CDKs to regulate Treslin-MTBP and plays a crucial in selecting which origins will undergo initiation."

Journal • MDM2 • TOPBP1

Population Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Kinase Inhibitor, in Patients With Advanced Solid Tumors. (PubMed, J Clin Pharmacol) - "Sex, age (36-88 years), race, and mild hepatic impairment had no impact on the CL/F of TAK-931. Taken together, the population PK analysis supports the same starting dose of TAK-931 in Asian and Western cancer patients in a global setting."

Clinical • Journal • PK/PD data • Hepatology • Oncology • Solid Tumor

A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery. (PubMed, Sci Adv) - "The efficacy of combination therapy in these cancer types was preclinically confirmed in the corresponding primary-derived xenograft models. Thus, our findings would be helpful to guide the future clinical strategies for TAK-931."

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

A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=44; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Trial primary completion date: Jun 2019 ➔ Nov 2019

Clinical • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • TP53

A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=44; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • TP53

A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=44; Not yet recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Initiation date: Nov 2018 ➔ Feb 2019

Clinical • Trial initiation date • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • TP53

A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=44; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Trial completion date: Mar 2021 ➔ Dec 2019

Clinical • Trial completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • TP53

A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=44; Not yet recruiting; Sponsor: Millennium Pharmaceuticals, Inc.

Clinical • New P1 trial • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • TP53

A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=20; Completed; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Completed; N=44 ➔ 20

Clinical • Enrollment change • Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • TP53