SY-1365

Decreasing Expression of Cancer-Driving Genes
AnneOvarian Cancer Survivor

Decreasing Expression of Cancer-Driving Genes

SY-1365 is a first-in-class potent and selective inhibitor of the cyclin-dependent kinase 7 (CDK7) that is in a Phase 1 clinical trial in patients with advanced solid tumors.

SY-1365 has shown significant anti-proliferative and pro-apoptotic activity in multiple preclinical models of difficult-to-treat solid tumors and blood cancers, including ovarian, breast and small cell lung cancers and acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). SY-1365 has induced anti-tumor activity in patient-derived xenograft models of ovarian cancer and breast cancer, including significant regressions at a twice weekly dosing regimen consistent with the initial regimen being used in the Phase 1 clinical trial. In preclinical studies, SY-1365 has also been shown to preferentially kill cancer cells over non-cancerous cells and can lower the expression of key cancer-driving genes.

Upon completing the dose escalation portion of the ongoing Phase 1 trial, we plan to expand the trial to focus initially on ovarian and breast cancers.

A Promising Approach for Difficult-to-Treat Cancers

Many cancers that are dependent on unusually high expression of transcription factors for their growth and survival have proven particularly difficult to treat, eluding targeted approaches to treatment. SY-1365 has the potential to address significant unmet needs for patients with a range of these transcriptionally dependent solid tumors and blood cancers.

Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer-related deaths among women, with only about 17% of women with ovarian cancer that has metastasized, or spread to other parts of the body, surviving five or more years from their diagnosis. Approximately 60,000 people diagnosed each year in the United States, Canada, Japan and five largest European countries. Despite the emergence of some targeted therapies for ovarian cancer, surgery, chemotherapy and radiation remain the standard of care and there remains a need for better treatment options.

Potent and Highly Selective CDK7 Inhibitor

Program Indication Discovery Preclinical Early Clinical Mid-Stage Clinical Pivotal Commercial Rights
SY-1365 (CDK7 inhibitor)
SY-1365 (CDK7 inhibitor)
Solid tumors dose escalation
Discovery Phase complete
Preclinical Phase complete
Early Clinical Phase in progress
Mid-Stage Clinical Phase not started
Pivotal Phase not started
Syros (Global)
Syros (Global)
SY-1365 (CDK7 inhibitor)
Ovarian cancer (single agent & combination with carboplatin)
Discovery Phase complete
Preclinical Phase in progress
Early Clinical Phase not started
Mid-Stage Clinical Phase not started
Pivotal Phase not started
Syros (Global)
SY-1365 (CDK7 inhibitor)
Breast cancer (combination with fulvestrant)
Discovery Phase complete
Preclinical Phase in progress
Early Clinical Phase not started
Mid-Stage Clinical Phase not started
Pivotal Phase not started
Syros (Global)

Our Publications

SY-1365 Publications

QUANTITATIVE CHIP-SEQ NORMALIZATION REVEALS GLOBAL MODULATION OF THE EPIGENOME

David A. Orlando, Mei Wei Chen, Victoria E. Brown, Snehakumari Solanki, Yoon J. Choi, Eric R. Olson,
Christian C. Fritz, James E. Bradner, and Matthew G. Guenther
Cell Reports, Volume 9, Issue 3, 1163 - 1170
2014

TARGETING TRANSCRIPTIONAL ADDICTIONS IN SMALL CELL LUNG CANCER WITH A COVALENT CDK7 INHIBITOR

Camilla L. Christensen, Nicholas Kwiatkowski, Brian J. Abraham, Julian Carretero, Fatima Al-Shahrour, Tinghu Zhang, Edmond Chipumuro, Grit S. Herter-Sprie, Esra A. Akbay, Abigail Altabef, Jianming Zhang, Takeshi Shimamura, Marzia Capelletti, Jakob B. Reibel, Jillian D. Cavanaugh, Peng Gao, Yan Liu, Signe R. Michaelsen, Hans S. Poulsen, Amir R. Aref, David A. Barbie, James E. Bradner, Rani E. George, Nathanael S. Gray, Richard A. Young, Kwok-Kin Wong.
Cancer Cell
doi: 10.1016/j.cell.2014.10.019
2014

CDK7-DEPENDENT TRANSCRIPTIONAL ADDICTION IN TRIPLE-NEGATIVE BREAST CANCER

Yuboa Wang, Tinghu Zhang, Nicholas Kwitowski, Brian J. Abraham, Tong Ihn Lee, Shaozhen Xie, Haluk Yuzugulu, Thanh Von, Heyuan Li, Ziao Lin, Daniel G. Stover, Elgene Lim, Zhiagang C. Wang, J.Dirk Iglehart, Richard A. Young, Nathanael S. Gray, Jean J. Zhao
Cell
doi:10.1016/j.cell.2015.08.063
2015

TARGETING TRANSCRIPTIONAL DEPENDENCY IN ACUTE MYELOID LEUKEMIA (AML) WITH A COVALENT INHIBITOR OF TRANSCRIPTIONAL KINASE CDK7

Yixuan Ren, Victoria Brown, Shanhu Hu, Jeremy Lopez, Sofija Miljovska, Darby Schmidt, Michael Bradley, Kevin Sprott, Eric Olson, Christian C. Fritz and, Yoon Jong Choi
ASH Annual Meeting: Session: 616, Poster I
2015

CDK7 INHIBITION AS A NOVEL TREATMENT STRATEGY FOR ACUTE LEUKEMIAS

Shanhu Hu, Nan Ke, Yixuan Ren, Jeremy Lopez, Sofija Miljovska, David Orlando, Darby Schmidt, Michael Bradley, Kevin Sprott, Eric Olson, Christian C. Fritz, and Yoon Jong Choi
AACR Annual Meeting
Poster Section: 20
Abstract Number: 4820
2016

FIRST-IN-CLASS CDK7 INHIBITOR, INDUCES ROBUST APOPTOSIS IN ACUTE MYELOID LEUKEMIA AND DEMONSTRATES DURABLE IN VIVO EFFICACY

Yoon Jong Choi, Shanhu Hu, Nan Ke, Yixuan Ren, Jeremy Lopez, Sofija Miljovska, David Orlando, Darby Schmidt, Michael Bradley, Kevin Sprott, Christian Fritz and Eric Olson
EHA 21st Congress
Poster Section: Biology 3
Abstract Number: P558
2016

SY-1365, A POTENT AND SELECTIVE CDK7 INHIBITOR, EXHBITS PROMISING ANTI-TUMOR ACTIVITY IN MULTIPLE PRECLNICAL MODELS OF AGGRESSIVE SOLID TUMORS

Shanhu Hu, Nan Ke, Yixuan Ren, Sofija Miljovska, Nisha Rajagopal, Michael McKeown, David Orlando, Kevin Sprott, Yoon Choi, Eric Olson and Christian Fritz
AACR Annual Meeting
Poster Section: 4
Abstract Number: 1151
2017

A PHASE 1 STUDY OF SY-1365, A SELECTIVE CDK7 INHIBITOR, IN ADULT PATIENTS WITH ADVANCED SOLID TUMORS

Anthony Tolcher, Khanh T. Do, Emmanuelle di Tomaso, Nigel J. Waters, Kristin Stephens, David A. Roth, Geoffrey Shapiro
ESMO Congress
Abstract Number: 425TiP
2017

SUPPRESSION OF ADAPTIVE RESPONSES TO TARGETED CANCER THERAPY BY TRANSCRIPTIONAL REPRESSION

Maria Rusan, Kapsok Li, Yvonne Li, Camilla L. Christensen, Brian J. Abraham, Nicholas Kwiatkowski, Kevin A. Buczkowski, Bruno Bockorny, Ting Chen, Shuai Li, Kevin Rhee, Haikuo Zhang, Wankun Chen, Hideki Terai, Tiffany Tavares, Alan L. Leggett, Tianxia Li, Yichen Wang, Tinghu Zhang, Tae-Jung Kim, Sook-Hee Hong, Neermala Poudel-Neupane, Michael Silkes, Tenny Mudianto, Li Tan, Takeshi Shimamura, Matthew Meyerson, Adam J. Bass, Hideo Watanabe, Nathanael S. Gray, Richard A. Young, Kwok-Kin Wong and Peter S. Hammerman
Cancer Discovery DOI: 10.1158/2159-8290.CD-17-0461
October 20, 2017

PK/PD MODELING OF THE FIRST-IN-CLASS, POTENT AND SELECTIVE COVALENT CDK7 INHIBITOR, SY-1365, PROVIDES MECHANISTIC BASIS FOR INTERMITTENT DOSING REGIMENS IN PRECLINICAL EFFICACY MODELS OF HEMATOLOGICAL AND SOLID TUMORS

Nigel J. Waters, Shanhu Hu, Brett Matzuka, Graeme Hodgson, Yixuan Ren, Yoon Choi, Kevin Dykstra, Christopher Roberts, Kevin Sprott, Emmanuelle di Tomaso, Christian C. Fritz
AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference
Abstract Number: B171
2017

BCL2L1 (BCLXL) EXPRESSION AND MYC SUPER-ENHANCER POSITIVITY PREDICT SENSITIVITY TO THE COVALENT CDK7 INHIBITOR SY-1365 IN TRIPLE NEGATIVE BREAST CANCER (TNBC) CELL LINES

Nisha Rajagopal, Graeme Hodgson, Liv Johannessen, Shanhu Hu, Nan Ke, Michael McKeown, Matthew Guenther, Alex Bush, Christian Fritz, David Orlando, Eric Olson, Emmanuelle di Tomaso
San Antonio Breast Cancer Symposium
Abstract Number: 1343
2017

SY-1365, A POTENT AND SELECTIVE CDK7 INHIBITOR, EXHIBITS ANTI-TUMOR ACTIVITY IN PRECLINICAL MODELS OF HEMATOLOGIC MALIGNANCIES AND DEMOSTRATES INTERACTIONS WITH THE BCLXL/BCL2 MITOCHONDRIAL APOPTOSIS SIGNALING PATHWAY IN LEUKEMIA

Graeme Hodgson, Liv Johannessen, Nisha Rajagopal, Shanhu Hu, David Orlando, Matthew Eaton, Michael McKeown, Jeffrey Tyner, Stephen Kurtz, Kevin Sprott, Christian Fritz, Emmanuelle di Tomaso
American Society of Hematology Annual Meeting
Abstract Number: 2651
2017

SY-1365, A SELECTIVE CDK7 INHIBITOR, EXHIBITS POTENT ANTI-TUMOR ACTIVITY AGAINST OVARIAN CANCER MODELS IN VITRO AND IN VIVO

Panagiotis A. Konstantinopoulos, Graeme Hodgson, Nisha Rajagopal, Liv Johannessen, Joyce F. Liu, Paul T. Kirschmeier, Shan Zhou, Cam Anh Tran, Nan Ke, David Orlando, Christian Fritz, Emmanuelle di Tomaso, Ursula A. Matulonis
American Association for Cancer Research (AACR) Annual Meeting: Poster Session
Abstract Number: 1525
2018

SY-1365, A SELECTIVE CDK7 INHIBITOR, EXHIBITS POTENT ANTI-TUMOR ACTIVITY AGAINST OVARIAN CANCER MODELS IN VITRO AND IN VIVO

Panagiotis A. Konstantinopoulos, Graeme Hodgson, Nisha Rajagopal, Liv Johannessen, Joyce F. Liu, Paul T. Kirschmeier, Shan Zhou, Cam Anh Tran, Nan Ke, David Orlando, Christian Fritz, Emmanuelle di Tomaso, Ursula A. Matulonis
American Association for Cancer Research (AACR) Annual Meeting: Poster Discussion Session
Abstract Number: 1525
2018

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

Geoffrey Shapiro, Kyriakos P. Papadopoulos, Khanh T. Do, Dejan Juric, Rinath Jeselsohn, Panagiotis Konstantinopoulos, Ursula Matulonis, Graeme Hodgson, Emmanuelle di Tomaso, Kristin Stephens, David A. Roth, Anthony Tolcher
American Society of Clinical Oncology (ASCO) Annual Meeting 
Abstract Number TPS2600
2018

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