SY-5609 / Syros - LARVOL DELTA

Preclinical efficacy of dual BET/HAT inhibitor–based combinations against post myeloproliferative neoplasm secondary AML cells (ASH 2025) - "Notably, treatment with BETi (e.g., OTX015) wasshown to reduce leukemia burden and improve survival in xenograft models of post-MPN sAML cells.However, BETi resistance and BETi-refractory disease develop uniformly...Compared to pan-BET inhibitor INCB057643,treatment with EP31670 induced significantly greater in vitro lethality in HEL92.1.7 and SET2 cells.Notably, in vitro treatment of cell lines and PD post-MPN sAML cells with EP31670 in combination withruxolitinib, for 72 to 96 hours induced synergistic lethality, as determined by SynergyFinder...Notably, co-treatment with EP31670 and SY-5609resulted in significantly greater reduction in leukemia burden and overall survival of the mice thantreatment with each agent alone (p < 0.05). These findings demonstrate promising preclinical activity ofEP31670 against cellular models of MPN-sAML and strongly support the rationale to further evaluate thein vivo efficacy of EP31670-based combinations against advanced MPN with..."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • ASXL1 • BCL2 • BRD4 • CALR • CDK6 • CDKN1A • DNMT3A • EP300 • HEXIM1 • IL6 • JAK2 • MYC • PIM1 • RUNX1 • STAT5 • STAT5AWqe • TP53

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

Functional insight into cyclin-dependent kinase (CDK)7 via chemical inhibition of the priority fungal pathogen Cryptococcus neoformans. (PubMed, mBio) - "The antifungal activity of SY-1365 was also markedly enhanced in combination with membrane-targeting antifungals. Together, our findings highlight CDK7 inhibitors as valuable tools to study CDK7 function in Cn and as potentially promising antifungals in combination with licensed antifungals."

Journal • CNS Disorders • Hematological Disorders • Hematological Malignancies • Human Immunodeficiency Virus • Infectious Disease • Leukemia • Oncology • Transplantation • CDK7

A potent CDK7 inhibitor TY-2699a suppresses palbociclib-resistant breast cancer and has the potential for combination with chemotherapy or immunotherapy in solid tumors (AACR 2025) - "The efficacy of CT-7001 monotherapy at a dose of 100 mg/kg was comparable to that of TY-2699a at a dose of 1 mg/kg, which only mildly inhibited tumor growth. Our efficacy data of TY-2669a provides a solid rationale for further evaluation of TY-2699a +/- fulvestrant in clinical HR+Her2- CDK4/6-resistant breast cancer patients. In addition, targeted inhibition of CDK7 not only enhanced the efficacy of paclitaxel or gemcitabine in pancreatic cancer cells, but also enhanced the in vivo efficacy of nab-paclitaxel, gemcitabine, and nab-paclitaxel in combination with gemcitabine in mouse pancreatic cancer tumor models...In the single-agent dose escalation stage, TY-2699a showed better clinical safety than SY-5609 did... TY-2699a was more than 80-, 66- and 86-fold more active than palbociclib in palbociclib-resistant stable cell lines of MCF7, T47D and HCC1428 cells, respectively. Consistent with the in vitro results, a 40 mg/kg dose of palbociclib almost completely failed to..."

IO biomarker • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Nasopharyngeal Carcinoma • Oncology • Pancreatic Cancer • Solid Tumor • CDK6 • ER • HER-2

Targeting transcriptional regulation using CDK7 and CDK9 inhibition as a novel combination therapy in fibrolamellar carcinoma (AACR 2025) - "Here, we show FLC has an increase in phosphorylated RPB1 specifically at s5 and s7, and a unique sensitivity to CDK7 inhibition with SY5609. The addition of CDK9 inhibition using VIP152 is synergistic at downregulating FLC specific driver genes and decreasing activated RPB1 and viability. Ongoing work is validating this combination in animal models to assess toxicity and in vivo efficacy."

Combination therapy • Biliary Cancer • Cholangiocarcinoma • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CDK7 • DNAJB1 • LINC00473 • PRKACA

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=542 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2029 ➔ Nov 2028

Trial completion date • Colorectal Cancer • Oncology • Solid Tumor

CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609. (PubMed, Int J Biol Macromol) - "Therefore, it can be used in structure-assisted design of CDK7 inhibitors, as demonstrated by the crystal structure of the complex with inhibitor SY5609. CDK2m7 thus represents a simple and affordable platform for CDK7 rational drug design."

Journal • Oncology • CCNA2 • CDK2 • CDK7

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=542 | Recruiting | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Recruiting

Enrollment open • Metastases • Colorectal Cancer • Oncology • Solid Tumor

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=422 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Apr 2026 ➔ Nov 2029 | Trial primary completion date: Sep 2025 ➔ Aug 2027 | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML. (PubMed, Blood) - "Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells.  A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML."

Journal • Preclinical • Acute Myelogenous Leukemia • Myeloproliferative Neoplasm • Oncology • BCL2L1 • BRD4 • CASP3 • CASP9 • CCND1 • CDK4 • CDK6 • CDKN1A • ITGAM • MYC • PIM1 • TP53

Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy. (PubMed, J Med Chem) - "To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds 2 and 3 using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset...Compound 13 exhibits potent in vitro activity, good ADME properties, and robust in vivo antitumor activity in xenograft models as a monotherapy. Notably, compound 13 with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects."

Journal • Gastrointestinal Disorder • Oncology

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=422 | Recruiting | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Recruiting

Enrollment open • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=422 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

CDK7 as a drug target in advanced stage uveal melanoma (AACR 2024) - "We tested a clinically relevant, highly specific CDK7 inhibitor, SY-5609, developed by Syros Pharmaceuticals and similarly showed that the cell lines were sensitive to the growth inhibitory effects of SY-5609. Furthermore, we observed synergistic effects on cell growth inhibition when combined with a MEK inhibitor (Trametinib)...These results are validated using a multi-omic approach, utilizing Reverse Phase Protein Array (RPPA) data to validate transcriptome to proteome expression of these enriched pathways. Overall, our studies indicate that targeting CDK7 in uveal melanoma is a potential treatment strategy for BAP1-deficient UM and enhances MEK inhibitor efficacy."

Metastases • Tumor mutational burden • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BAP1 • CDK7 • IFNG • TGFB1 • TMB

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=422 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Aug 2026 ➔ Apr 2026

Metastases • Trial completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=105 | Completed | Sponsor: Syros Pharmaceuticals | Active, not recruiting ➔ Completed | N=160 ➔ 105 | Trial completion date: Jul 2024 ➔ Mar 2023 | Trial primary completion date: Jul 2023 ➔ Jan 2023

Enrollment change • Metastases • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Gastrointestinal Cancer • Hepatology • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • HER-2

Cyclin-Dependent Kinase 7 (CDK7) Is a Novel Target in Fibrolamellar Carcinoma (ACS-CLINCON 2023) - "CDK7 inhibition was achieved with a selective inhibitor (SY5609). This is the first study to discern an aberrant pathway in human FLC that regulates FLC-specific gene expression (outside of DNAJB1-PRKACA). Given the lethal impact in FLC cells and low cytotoxicity in PHHs with CDK7 inhibition, we have identified a strong candidate for therapy in FLC."

Hepatocellular Cancer • Hepatology • Oncology • CDK7 • DNAJB1 • PRKACA

Tolerability and preliminary activity of the potent, selective, oral CDK7 inhibitor SY-5609 in combination with fulvestrant in patients with advanced hormone receptor-positive (HR+), HER2- breast cancer (BC). (ASCO 2023) - P1 | "SY-5609 + fulvestrant has an acceptable safety profile consistent with SA SY-5609 or fulvestrant. The mechanistic rationale for CDK7 inhibition in HR+, HER2- BC and the tolerability and encouraging early activity in this heavily pretreated population support future investigation of SY-5609 in combination with SERDs, including defining the maximum tolerated combination dose using the 7/7 SY-5609 schedule. Clinical trial information: NCT04247126."

Clinical • Combination therapy • Metastases • Breast Cancer • Fatigue • Hematological Disorders • Hepatology • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Thrombocytopenia • HER-2 • TP53

Phase 1/1b study of SY-5609, a selective and potent CDK7 inhibitor, in advanced solid tumors and in 2L/3L pancreatic ductal adenocarcinoma (PDAC) in combination with gemcitabine +/- nab-paclitaxel. (ASCO 2023) - P1 | "To date, intermittent dosing of SY-5609 on the 7/7 schedule has acceptable tolerability alone and in combination with gem +/- np. Encouraging preliminary clinical activity and the emerging exposure-activity relationship supports the ongoing escalation of SY-5609 in SA and combination SLI cohorts; updated results will be presented. Clinical trial information: NCT04247126."

Combination therapy • Metastases • P1 data • Anorexia • Constipation • Fatigue • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Oncology • Pain • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Thrombocytopenia • CDK7

Syros Presents Data from Phase 1/1b Clinical Trial of SY-5609 in Advanced Solid Tumors at ASCO Annual Meeting (Businesswire) - P1/1b | N=160 | NCT04247126 | Sponsor: Syros Pharmaceuticals | "Syros will present updated data from the single agent dose escalation portion and the gemcitabine/nab-paclitaxel combination safety lead-in portion of the Phase 1/1b trial. The maximum tolerated dose (MTD) of SY-5609 as a single-agent was 10 mg using a 7 day on/7 day off dosing schedule....Encouraging clinical activity was observed at the MTDs with SY-5609 both as a single-agent (10 mg) and in combination (4 or 5 mg plus gemcitabine). Among the three response evaluable patients with select solid tumors, which included one patient with PDAC, data demonstrated a 100% disease control rate (DCR) with 10 mg SY-5609 monotherapy, with the PDAC patient experiencing a 10% tumor reduction. Of the nine PDAC patients treated with 4 or 5 mg of SY-5609 in combination with gemcitabine, the data demonstrated a 44% DCR (four patients)."

P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Syros Presents Data from Phase 1/1b Clinical Trial of SY-5609 in Advanced Solid Tumors at ASCO Annual Meeting (Businesswire) - P1/1b | N=160 | NCT04247126 | Sponsor: Syros Pharmaceuticals | "Syros will present data from the fulvestrant combination cohort. Patients enrolled in this cohort presented with advanced disease: 78.6% (11 of 14 patients) had liver metastases and were heavily pre-treated: 78.6% (11 of 14 patients) had received ≥5 prior therapies, 100% (14 of 14 patients) had progressed on CDK4/6 therapy, and 85.7% (12 of 14 patients) had received prior fulvestrant....An MTD was not established. Twelve patients were evaluable for response across a range of doses and dosing schedules. Five of 12 achieved stable disease for a DCR of 42%; three of these five patients achieved target lesion regression. Three patients remained on treatment with SD for greater than six months, including patients with the TP53 mutation, prior fulvestrant exposure and/or liver disease."

P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC) (clinicaltrials.gov) - P1 | N=340 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jan 2026 ➔ Aug 2026

Metastases • Trial completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

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

TY-2699a is a highly potent CDK7 inhibitor to abolish dysfunctional tumor cell cycle for clinical development (AACR 2023) - P1 | "Currently, trilaciclib, palbociclib, ribociclib, and abemaciclib that bear dual specificities against CDK4 and CDK6 have been approved for clinical usage, and more CDK4/6 targeted agents are actively under clinical evaluations, among which, TY-302, a novel CDK4/6 inhibitor being developed by TYK Medicines, is under Phase II trial (NCT04433494)...Several CDK7 targeted agents, such as SY-5609 and Samuraciclib (CT7001), are under development...# Shengli Dong and Apeng Liang contributed equally to this work. * Jun Li, Shengli Dong and Apeng Liang are the correspondent authors."

Clinical • Tumor cell • Acute Myelogenous Leukemia • Breast Cancer • Gastrointestinal Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Ovarian Cancer • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • CCNA2 • CCND1 • CCNE1 • CDK1 • CDK2 • CDK7

Automated organoid alignment for clonal response characterization in pancreatic ductal adenocarcinoma (AACR 2023) - "This analysis was performed in drug screen of 80 independent agents in early clinical trials in combination with CDK7 inhibitor, SY-5609... We provide a method for high fidelity alignment of PCOs in low-volume format for matrix-based screening applications. These techniques can be adapted to existing staining protocols to characterize subclonal response in the context of both molecular heterogeneity and clinical outcomes."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma