SY-1365

Decreasing Expression of Oncogenic Transcription Factors
AnneOvarian Cancer Survivor

Decreasing Expression of Oncogenic Transcription Factors

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, including cancers such as triple negative breast, small cell lung and ovarian cancers that are dependent on unusually high expression of transcription factors for their growth and survival.

SY-1365 has shown significant anti-proliferative and pro-apoptotic activity in multiple preclinical models of difficult-to-treat solid tumors, including triple negative breast, small cell lung and ovarian cancers. SY-1365 has induced anti-tumor activity in both cell line-derived xenograft and patient-derived xenograft models of triple negative 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 models, SY-1365 has also been shown to preferentially kill cancer cells over non-cancerous cells and can lower the expression of oncogenic transcription factors, including MYC.

Upon establishing the appropriate dose in the ongoing Phase 1 trial, we plan to expand development of SY-1365 into acute leukemia, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

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.

Transcriptionally Dependent Solid Tumors

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.

Small cell lung cancer (SCLC) represents approximately 13-18% of all lung cancers, with about 65,000 people diagnosed each year in the United States, Canada, Japan and five largest European countries. It is the most aggressive among lung cancers, with only about 2% of patients with metastatic SCLC surviving five or more years from their diagnosis. There have been few advances in the treatment of SCLC in recent years, with surgery, chemotherapy and radiation remaining the standard of care.

Triple negative breast cancer (TNBC) represents approximately 15-20% of all breast cancers, with about 42,000 people diagnosed each year in the United States, Canada, Japan and five largest European countries. It tends to be more aggressive than other forms of breast cancer, with a poorer prognosis. Despite significant advances in the treatment of certain subtypes of breast cancer, the treatment of TNBC has seen few advances in recent years, with surgery, chemotherapy and radiation remain the standard of care for TNBC.

Acute Leukemia

Acute leukemia, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), remains a significant unmet need. More than 37,000 people are diagnosed with AML each year in the United States, Canada, Japan and five largest European countries, with only 27% of AML patients surviving five or more years from their diagnosis. Few new treatment options have been approved in the last 20 years, with older chemotherapeutics and stem cell transplantation remaining the standard of care. Approximately 12,000 people are diagnosed with ALL each year in the United States, Canada, Japan and five largest European countries. While the cure rate for ALL patients under the age of 20 is high, about 40% of those diagnosed with ALL are older than 20 and only half of these patients are cured, highlighting the need for more effective therapies. As with AML, there have been few advances in the treatment of ALL in recent years, with chemotherapy and stem cell transplantation remaining the standard of care.

Potent and Highly Selective CDK7 Inhibitor

Program Indication Preclinical Early Clinical Mid-Stage Clinical Pivotal Commercial Rights
SY-1365 (CDK7 inhibitor)
SY-1365 (CDK7 inhibitor)
Solid Tumors (TNBC, Ovarian, SCLC)
Preclinical Phase complete
Early Clinical Phase in progress
Mid-Stage Clinical Phase not started
Pivotal Phase not started
Worldwide
Worldwide
SY-1365 (CDK7 inhibitor)
Acute Leukemia (AML and ALL)
Preclinical Phase in progress
Early Clinical Phase not started
Mid-Stage Clinical Phase not started
Pivotal Phase not started
Worldwide

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

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