^
2d
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.
Preclinical • Journal
|
TP53 (Tumor protein P53) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • BCL2L1 (BCL2-like 1) • CDK6 (Cyclin-dependent kinase 6) • CASP3 (Caspase 3) • PIM1 (Pim-1 Proto-Oncogene) • ITGAM (Integrin, alpha M) • BRD4 (Bromodomain Containing 4) • CASP9 (Caspase 9) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
MYC expression • CCND1 expression
|
Jakafi (ruxolitinib) • birabresib (OTX015) • SY-5609 • pelabresib (DAK539)
25d
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, Hoffmann-La Roche | Trial completion date: Apr 2026 --> Nov 2029 | Trial primary completion date: Sep 2025 --> Aug 2027 | Recruiting --> Active, not recruiting
Enrollment closed • Trial completion date • Trial primary completion date • Metastases
|
Avastin (bevacizumab) • Erbitux (cetuximab) • Tecentriq (atezolizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • divarasib (RG6330) • Itovebi (inavolisib) • SY-5609 • tiragolumab (RG6058)
2ms
Enrollment open • Metastases
|
Avastin (bevacizumab) • Erbitux (cetuximab) • Tecentriq (atezolizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • divarasib (RG6330) • Itovebi (inavolisib) • SY-5609 • tiragolumab (RG6058)
5ms
Enrollment closed • Metastases
|
Avastin (bevacizumab) • Erbitux (cetuximab) • Tecentriq (atezolizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • divarasib (RG6330) • Itovebi (inavolisib) • SY-5609 • tiragolumab (RG6058)
9ms
Trial completion date • Metastases
|
Avastin (bevacizumab) • Erbitux (cetuximab) • Tecentriq (atezolizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • divarasib (RG6330) • Itovebi (inavolisib) • SY-5609 • tiragolumab (RG6058)
1year
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 further evaluate in vivo efficacy of CDK7i-based combinations against advanced MPN with excess blasts or MPN-sAML.
Preclinical • PARP Biomarker • Metastases
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • CDK4 (Cyclin-dependent kinase 4) • BCL2L1 (BCL2-like 1) • SRSF2 (Serine and arginine rich splicing factor 2) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD34 (CD34 molecule) • CDK6 (Cyclin-dependent kinase 6) • AURKA (Aurora kinase A) • PLK1 (Polo Like Kinase 1) • PIM1 (Pim-1 Proto-Oncogene) • ITGAM (Integrin, alpha M) • TGFB1 (Transforming Growth Factor Beta 1) • BRD4 (Bromodomain Containing 4) • CALR (Calreticulin) • CASP9 (Caspase 9) • CDK9 (Cyclin Dependent Kinase 9) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • CD99 (CD99 Molecule) • CDK1 (Cyclin-dependent kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1) • CLEC12A (C-Type Lectin Domain Family 12 Member A)
|
TP53 mutation • JAK2 V617F
|
Venclexta (venetoclax) • Jakafi (ruxolitinib) • birabresib (OTX015) • ABBV-744 • SY-5609 • pelabresib (DAK539) • mevociclib (SY-1365)
1year
A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors (clinicaltrials.gov)
P1, N=105, Completed, Syros Pharmaceuticals | Active, not recruiting --> Completed | N=160 --> 105 | Trial completion date: Jul 2024 --> Mar 2023 | Trial primary completion date: Jul 2023 --> Jan 2023
Trial completion • Enrollment change • Trial completion date • Trial primary completion date • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HR positive • HER-2 negative
|
gemcitabine • albumin-bound paclitaxel • fulvestrant • SY-5609
over1year
Trial completion date • Metastases
|
Avastin (bevacizumab) • Erbitux (cetuximab) • Tecentriq (atezolizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • divarasib (RG6330) • Itovebi (inavolisib) • SY-5609 • tiragolumab (RG6058)
over1year
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)
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
|
HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53)
|
TP53 mutation • HR positive • HER-2 negative
|
fulvestrant • SY-5609
over1year
TY-2699a is a highly potent CDK7 inhibitor to abolish dysfunctional tumor cell cycle for clinical development (AACR 2023)
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
|
CCND1 (Cyclin D1) • CCNE1 (Cyclin E1) • CCNA2 (Cyclin A2) • CDK2 (Cyclin-dependent kinase 2) • CDK7 (Cyclin Dependent Kinase 7) • CDK1 (Cyclin-dependent kinase 1)
|
CDK7 overexpression
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • Cosela (trilaciclib) • SY-5609 • samuraciclib (CT7001) • TY-2699a • TY-302
over1year
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.
Preclinical • PARP Biomarker • Metastases
|
TP53 (Tumor protein P53) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • MCL1 (Myeloid cell leukemia 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • IL6 (Interleukin 6) • CDK4 (Cyclin-dependent kinase 4) • BCL2L1 (BCL2-like 1) • SRSF2 (Serine and arginine rich splicing factor 2) • CD34 (CD34 molecule) • PIM1 (Pim-1 Proto-Oncogene) • CALR (Calreticulin) • CDK9 (Cyclin Dependent Kinase 9) • CDK1 (Cyclin-dependent kinase 1)
|
MYC expression
|
Venclexta (venetoclax) • Jakafi (ruxolitinib) • birabresib (OTX015) • SY-5609 • mevociclib (SY-1365)
over1year
A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors (clinicaltrials.gov)
P1, N=160, Active, not recruiting, Syros Pharmaceuticals | Recruiting --> Active, not recruiting
Enrollment closed • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HR positive • HER-2 negative
|
gemcitabine • albumin-bound paclitaxel • fulvestrant • SY-5609
almost3years
Enrollment change
|
HER-2 (Human epidermal growth factor receptor 2)
|
HR positive • HER-2 negative
|
gemcitabine • albumin-bound paclitaxel • fulvestrant • SY-5609
3years
SY5609, a Potent and Selective CDK7 Inhibitor, Potentiates BTK Inhibitor Activity in Mantle Cell Lymphoma Preclinical Models (ASH 2021)
SY-5609 is a potent and selective CDK7 inhibitor that demonstrates antiproliferative activity in MCL cells in vitro , associated with PD changes comparable to those observed in patients enrolled in the SY-5609 solid tumor trial (ENA, 2020). The combination of SY-5609 and acalabrutinib is synergistic in MCL cells in vitro and inhibits expression of key cell cycle regulatory proteins CCND1 and E2F1 at concentrations that are preclinically subtherapeutic for either single agent alone. The combination of SY-5609 and acalabrutinib is also significantly more effective at inhibiting MCL xenograft growth in vivo than either single agent.
Preclinical
|
ER (Estrogen receptor) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • CCND1 (Cyclin D1) • E2F1 (E2F transcription factor 1)
|
CCND1 expression
|
Calquence (acalabrutinib) • SY-5609
3years
A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors (clinicaltrials.gov)
P1, N=80, Recruiting, Syros Pharmaceuticals | Trial completion date: Jan 2023 --> Jul 2024 | Trial primary completion date: Jun 2021 --> Jul 2023
Clinical • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2)
|
HR positive • HER-2 negative
|
fulvestrant • SY-5609
over3years
[VIRTUAL] SY-5609, a highly potent and selective oral CDK7 inhibitor, exhibits robust antitumor activity in preclinical models of KRAS mutant cancers as a single agent and in combination with chemotherapy (ESMO 2021)
PDAC studies were done in RAS-mutant (7 KRAS, 1 NRAS) patient derived xenograft (PDX) models, and Panc-1 (KRAS-G12D) cells and xenografts +/- gemcitabine (Gem). NSCLC studies were done in A549 (KRAS G12S) cells and xenografts, and ST2972 (KRAS G12C) PDX tumors +/- docetaxel (Doc). In RAS-mutant PDAC PDX models derived from previously treated patients, SA SY-5609 (6mpk QD x28) induced regressions in 50% (4/8) of models and was well-tolerated (average body weight change [avg-BWC] 0%); regressions were sustained ≥2 weeks (wks) after drug discontinuation... SY-5609 shows robust antitumor activity in RAS-mutant PDAC and NSCLC preclinical models. support clinical evaluation of SY-5609 in combination with Gem in PDAC and Doc in NSCLC.
Preclinical • Combination therapy
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
KRAS mutation • KRAS G12C • NRAS mutation • KRAS G12D • KRAS G12 • KRAS G12S • NRAS G12D • NRAS G12S
|
gemcitabine • docetaxel • SY-5609
over4years
Clinical • Enrollment change
|
HER-2 (Human epidermal growth factor receptor 2)
|
HR positive • HER-2 negative
|
fulvestrant • SY-5609
over4years
[VIRTUAL] Activity of SY-5609, an oral, noncovalent, potent, and selective CDK7 inhibitor, in preclinical models of colorectal cancer. (ASCO 2020)
Daily oral dosing of the CDK7 inhibitor SY-5609 induces robust TGI, including regressions, in CRC PDX models at well-tolerated doses. Dose-dependent TGI is associated with dose-dependent PD changes in CRC PDX tumor tissue. These results highlight the therapeutic potential of SY-5609 in CRC and support the evaluation of SY-5609 in CRC patients in early phase clinical trials.
Preclinical
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • CDK1 (Cyclin-dependent kinase 1)
|
KRAS mutation • BRAF mutation
|
SY-5609