mevociclib (SY-1365) / Syros - LARVOL DELTA

Pre-Clinical Efficacy of CDK7 Inhibitor-Based Combinations in Cellular Models of Advanced Myeloproliferative Neoplasms (MPN) Transformed to AML (ASH 2023) - "Treatment with JAK inhibitor (JAKi), e.g., ruxolitinib, venetoclax or hypomethylating agents alone or in combination are ineffective in improving the poor survival in MPN-sAML...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and clinical grade SY-5609, dose-dependently (20 to 250 nM) increased % G1 while reducing the % of cell-cycle S phase SET2 and HEL cells...SY-5609 treatment also exerted synergistic lethality with the BETi pelabresib or BD2-selective BETi ABBV-744 or the CBP/p300 inhibitor GNE-049 in MPN-sAML cells...Additionally, compared to each drug or vehicle control, co-treatment with SY-5609 and OTX015 (30 mg/kg/day by oral gavage) reduced more MPN-sAML burden and significantly improved survival in a HEL-Luc/GFP xenograft model without inducing toxicity. These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to..."

Metastases • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ASXL1 • AURKA • BCL2L1 • BRD4 • CALR • CASP9 • CCND1 • CD123 • CD34 • CD99 • CDK1 • CDK4 • CDK6 • CDK9 • CDKN1A • CLEC12A • HEXIM1 • IL3RA • ITGAM • JAK2 • MCL1 • MYC • PIM1 • PLK1 • RUNX1 • SRSF2 • STAT5 • TET2 • TGFB1

Preclinical efficacy of CDK7 inhibitor-based combinations in cellular models of advanced myeloproliferative neoplasms (MPN) (AACR 2023) - "Treatment with JAK inhibitors (JAKis), e.g., ruxolitinib, venetoclax and hypomethylating agents are ineffective in improving survival in MPN-BP...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and its clinical grade counterpart SY-5609, dose-dependently inhibits cell cycle, growth and induces lethality in SET2 and HEL as well as patient-derived (PD), CD34+ MPN-sAML cells...Co-treatment with CDK7i and ruxolitinib or the BET inhibitor OTX015 was synergistically lethal in PD MPN-BP cells (n=7). In an aggressive xenograft model of HEL-GFP/Luc cells in NSG mice, compared to the vehicle control, monotherapy with SY5609 significantly reduced the MPN sAML burden and improved survival of the NSG mice without causing host toxicity. These findings demonstrate promising activity and support the rationale to further evaluate the in vivo efficacy of CDK7i-based combinations against advanced MPN."

Metastases • Preclinical • Acute Myelogenous Leukemia • Myeloproliferative Neoplasm • Oncology • ASXL1 • BCL2L1 • CALR • CD34 • CDK1 • CDK4 • CDK9 • DNMT3A • IL6 • JAK2 • MCL1 • MYC • PIM1 • RUNX1 • SRSF2 • STAT5 • TET2 • TP53

Sy-1365, a Potent and Selective CDK7 Inhibitor, Exhibits Anti-Tumor Activity in Preclinical Models of Hematologic Malignancies, and Demonstrates Interactions with the BCL-XL/BCL2 Mitochondrial Apoptosis Signaling Pathway in Leukemia (ASH 2017) - P1; "SY-1365 shows potent in vitro inhibitory activity in multiple hematological indications and can induce AML xenograft tumor regression in mice. In vitro exploratory biomarker and tumor cell inhibitory combination studies in AML suggest a role for mitochondrial apoptosis signaling in mediating sensitivity to SY-1365 and support the evaluation of a combination with venetoclax. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors (NCT03134638)."

Acute Myelogenous Leukemia • Biosimilar • Lymphoma

BCL2L1 (BCL-XL) expression and MYC super-enhancer positivity predict sensitivity to the covalent CDK7 inhibitor SY-1365 in triple negative breast cancer (TNBC) cell lines (SABCS 2017) - P1; "These observations have generated strong hypotheses for selection strategies aimed at identifying patients with tumors particularly sensitive to CDK7 inhibition with SY-1365, and warrant further investigation with respect to predictive biomarkers of response in patients. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors, including a planned expansion cohort enriching for patients with TNBC (NCT03134638)."

Triple Negative Breast Cancer

Early Results from the Phase I Study of SY-1365, a Potent and Selective CDK7 inhibitor, in Patients with Ovarian Cancer and Advanced Solid Tumors (ESMO Asia 2019) - P1; "Background: SY-1365 is a first-in-class, potent, selective covalent CDK7 inhibitor currently under phase I evaluation in expansion cohorts including ovarian cancer (OC) patients (pts) to assess safety, biologic and anti-tumor activity of SY-1365 alone and in combination with carboplatin (CP), and correlation of activity with RB pathway changes (RbC). Emerging tolerability findings suggest predominantly low grade, reversible AEs, primarily on days of dosing. Early clinical activity demonstrates SD in both SA and CP combination cohorts with evidence supporting increased apoptosis in tumor tissue and associations of clinical activity with RbC. PK/PD guided dose optimization is in progress."

Clinical • P1 data • Gynecologic Cancers • Hematological Disorders • Oncology • Ovarian Cancer • Pain • Solid Tumor • Thrombocytopenia

Proof-of-Mechanism Based on Target Engagement and Modulation of Gene Expression Following Treatment with SY-1365, a First-in-Class Selective CDK7 Inhibitor in Phase 1 Patients with Advanced Cancer (EORTC-NCI-AACR 2018) - P1; "SY-1365 is a first-in-class selective and potent inhibitor of CDK7 in ph1 clinical development (NCT03134638). Doses ranging from 2 to 64 mg/m2 demonstrated linear PK without accumulation. Proof of mechanism was established based on CDK7 target occupancy and dose-dependent modulation of gene expression in PBMCs at tolerable doses where AEs were predominantly low grade, reversible and generally manageable."

Clinical • P1 data • Gynecologic Cancers • Oncology • Ovarian Cancer

SY-1365, a selective CDK7 inhibitor, enhances carboplatin activity in ovarian cancer cell lines and xenografts, and transcriptionally inhibits homologous recombination repair (HRR) genes (EORTC-NCI-AACR 2018) - P1; "SY-1365 is synergistic with CP in OC cell lines in vitro and enhances CP activity in OC xenografts in vivo. SY-1365 transcriptionally downregulates key mediators of the HRR pathway, including BRCA1/2, in OC cell lines in vitro. Taken together these results suggest that SY-1365 may impede DNA damage responses and DNA repair in OC patients, and support the potential for combination strategies aimed at exploiting this mechanism of action."

BRCA Biomarker • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

An oral and selective CDK7 inhibitor demonstrates substantial anti-tumor effect in breast and ovarian cancer models (EORTC-NCI-AACR 2018) - P1; "...SY-1365 is an IV administered CDK7 inhibitor and currently in phase I clinical study (NCT03134638)... We designed and profiled orally available, CDK7 selective inhibitors with potent activity against TNBC and OVA cells and induced tumor growth inhibition in breast cancer cell and patient derived xenograft models. These data support the rationale for advancing one or more members of this class toward clinical development."

Preclinical • Breast Cancer • Ovarian Cancer • Triple Negative Breast Cancer

Prospective identification of RB pathway alterations predict response to SY-1365, a selective CDK7 inhibitor, in a panel of high-grade serous ovarian cancer (HGSOC) patient derived xenograft (PDX) models (AACR 2019) - P1; "RB pathway alterations are predictive of response to SY-1365 in HGSOC PDX models. The results support exploration of RB pathway changes as predictive biomarkers of SY-1365 clinical activity in patients with ovarian cancer. SY-1365 is currently being assessed in a phase 1 trial in adult patients with ovarian and breast cancers (NCT03134638)."

Clinical

SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo (AACR 2018) - P1; "SY-1365 induces cytotoxicity in ovarian carcinoma cell lines and induces robust responses in heavily pretreated (including PARP-inhibitor and platinum-resistant) ovarian PDX models. Alterations in expression of mitochondrial apoptosis antagonists and RB pathway regulators are associated with SY-1365 response and support exploration of these as predictive biomarkers of SY-1365 clinical activity in ovarian carcinoma. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors."

IO Biomarker • PARP Biomarker • Preclinical • Ovarian Cancer

SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo (AACR 2018) - P1; "SY-1365 induces cytotoxicity in ovarian carcinoma cell lines and induces robust responses in heavily pretreated (including PARP-inhibitor and platinum-resistant) ovarian PDX models. Alterations in expression of mitochondrial apoptosis antagonists and RB pathway regulators are associated with SY-1365 response and support exploration of these as predictive biomarkers of SY-1365 clinical activity in ovarian carcinoma. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors ."

IO Biomarker • PARP Biomarker • Preclinical • Ovarian Cancer

Trial design of a first-in-human phase 1 evaluation of SY-1365, a first-in-class selective CDK7 inhibitor, with initial expansions in ovarian and breast cancer. (ASCO 2018) - P1; "The expansion phase will evaluate preliminary antitumor activity in 3 ovarian cancer cohorts, either as a single agent or in combination with carboplatin, an HR+ breast cancer cohort in combination with fulvestrant in pts who failed treatment with a CDK4/6 inhibitor in combination with an AI, and a cohort in pts with tumors of any histology to evaluate PD endpoints in paired tumor biopsies. Biological impact of SY-1365 will be assessed by quantifying gene expression and induction of tumor cell apoptosis when feasible. This trial opened in May 2017."

P1 data • Hormone Receptor Breast Cancer • Ovarian Cancer

TGF-β/Activin Signaling Promotes CDK7 Inhibitor Resistance in Triple Negative Breast Cancer Cells through Upregulation of Multidrug Transporters. (PubMed, J Biol Chem) - "Lastly, pharmacological inhibition of TGF-β/activin receptors or genetic silencing of SMAD4, a transcriptional partner of SMAD3, reversed the upregulation of ABCG2 in resistant cells and phenocopied ABCG2 inhibition. This study reveals that inhibiting the TGF-β/Activin-ABCG2 pathway is a potential avenue for preventing or overcoming resistance to CDK7 inhibitors."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ABCG2 • SMAD3 • SMAD4 • TGFB1

A Study of SY-1365 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=107; Terminated; Sponsor: Syros Pharmaceuticals; Trial completion date: Jun 2022 ➔ Jun 2020; Active, not recruiting ➔ Terminated; Business Decision

Clinical • Trial completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CDK7 • HER-2

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019). (PubMed, Bioorg Med Chem Lett) - "Significant clinical activity for the treatment of hormone receptor positive metastatic breast cancer has been demonstrated by palbociclib, ribociclib and abemaciclib, dual CDK4/6 inhibitors recently FDA-approved. SY-1365, a CDK7 inhibitor has shown initial encouraging data in phase I for solid tumors treatment. These results have rejuvenated the CDKs research field. This review provides an overview of relevant advances on CDK inhibitor research since 2015 to 2019, with special emphasis on transcriptional CDK inhibitors, new emerging strategies such as target protein degradation and compounds under clinical evaluation."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Syros reports third quarter 2018 financial results and highlights key accomplishments and upcoming milestones (Syros Press Release) - "Syros plans to present initial clinical data from cohorts in its Phase 2 trial evaluating the safety and efficacy of SY-1425 in combination with azacitidine in RARA and IRF8 biomarker-positive patients with newly diagnosed acute myeloid leukemia (AML)...at the 2018 American Society of Hematology (ASH) Annual Meeting...Syros plans to present clinical data from the dose escalation portion of its Phase 1 trial of SY-1365 in patients with advanced solid tumors...at the 30th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium...Syros plans to present new preclinical data showing the mechanistic rationale for the ongoing clinical evaluation of SY-1365..."

P1 data • P2 data • Preclinical • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Oncology • Solid Tumor

Syros to present clinical and preclinical data on SY-1365 and earlier-stage pipeline at EORTC-NCI-AACR Meeting (Syros Press Release) - P1, N=117; NCT03134638; Sponsor: Syros Pharmaceuticals; "Syros Pharmaceuticals...announced that the Company will present data from the dose escalation portion of its Phase 1 trial of SY-1365...in advanced solid tumor patients in an oral plenary session at the 30th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium taking place November 13-16 in Dublin...Syros will present new preclinical data on the mechanistic rationale for SY-1365 in combination with carboplatin in ovarian cancer..."

P1 data • Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

CDK7 inhibitors as anticancer drugs. (PubMed, Cancer Metastasis Rev) - P1, P1/2, P1a/1b | "Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494."

Journal • Review

Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7. (PubMed, Cancer Res) - P1 | "SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Anti-tumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematological and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers."

IO Biomarker • Journal • Acute Myelogenous Leukemia • Breast Cancer • Gynecologic Cancers • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Ovarian Cancer • Solid Tumor

CDK7 Inhibitors in Cancer Therapy: The Sweet Smell of Success? (PubMed, J Med Chem) - "Indeed, development of CDK7 inhibitors has gained huge momentum with two molecules, CT7001 and SY-1365, currently under clinical development. Herein, we discuss the latest understanding of the role of CDK7 in cancer cells and provide an overview of the pharmacophores of CDK7 inhibitors, their efficacy in various cancer models, and their clinical development."

Journal

A Study of SY-1365 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=137; Active, not recruiting; Sponsor: Syros Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Syros announces update on selective CDK7 inhibitor portfolio (Businesswire) - "Syros Pharmaceuticals...provided an update on its portfolio of selective cyclin-dependent kinase 7 (CDK7) inhibitors. The Company has decided to prioritize the development of its highly selective and potent oral CDK7 inhibitor, SY-5609, and to discontinue further development of SY-1365, its intravenous (IV) CDK7 inhibitor. Syros expects to initiate a Phase 1 clinical trial of SY-5609 in patients with select solid tumors in the first quarter of 2020."

Discontinued

"$SYRS Discontinuing Further Development of SY-1365, Its Intravenous CDK7 Inhibitor" (@BioStocks)

Syros reports second quarter 2019 financial results and highlights key accomplishments and upcoming milestones (Businesswire) - “Syros plans to report initial clinical data in the fourth quarter of 2019 from the expansion portion of its Phase 1 trial, including: initial efficacy and safety assessments…initial safety and pharmacokinetic data from the cohort evaluating SY-1365 in combination with carboplatin in high-grade serous ovarian cancer patients who have had one or more prior lines of therapy; and initial safety, efficacy and mechanistic data from the cohort evaluating SY-1365 as a single agent in patients with advanced solid tumors accessible for biopsy…proof-of-concept data from the ongoing cohort in high-grade serous ovarian cancer patients who have had three or more prior lines of therapy, in 2020...initial data from an ongoing cohort in hormone receptor (HR)-positive CDK4/6 inhibitor-resistant breast cancer patients in 2020.”

P1 data

New publication in cancer research highlights discovery of SY-1365, a first-in-class selective CDK7 inhibitor, and its promise as a potentially transformative targeted approach for difficult-to-treat cancers (Businesswire) - “Syros Pharmaceuticals…announced the online publication of a new manuscript, Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7, in the American Association for Cancer Research’s (AACR) journal, Cancer Research….This publication highlights the discovery, mechanism of action and promise of SY-1365 as a new targeted approach for a range of difficult-to-treat cancers.”

Clinical data