Overview
TY-2699a is a novel small molecule kinase inhibitor, independently developed by TYK Medicines, Inc, designed to selectively target CDK7 with good oral bioavailability. This innovative drug is intended for the treatment of various types of cancer, including breast cancer, ovarian cancer, and other solid tumors, as well as hematological cancers. The pre-clinical pharmacokinetics studies and safety evaluations have demonstrated favorable druggability and safety profiles for TY-2699a. In February 2023, TY-2699a received the SMP letter from the FDA, and in May 2023, it obtained approval of the clinical trial notice from the CDE. TY-2699a is the first Chinese CDK7 inhibitor to receive IND clearance from both the FDA and the CDE.
Mechanism of Action
CDK7 is a type of cyclin-dependent kinase (CDK), also a subunit of the general transcription factor TFIIH. The CDK-activating kinase (CAK) is a complex composed of CDK7, cyclin H, and the activating subunit MAT1. The CAK complex is responsible for activating CDKs and is involved in the regulation of cell cycle progression through phosphorylating the T-loop of CDK1, CDK2, CDK4, and CDK 6 and plays a crucial role in transcription and regulation during the cell cycle as part of the general transcription factor TFIIH. It is associated with various types of tumorigeneses with abnormal transcription control (such as MYC or ESR1 activation) or abnormal cell cycle control (such as changes in RB1, CCNE1, and CDKN2A). CDK7 overexpression has been identified in a wide spectrum of tumor tissues including triple negative breast cancer (TNBC), ovarian carcinoma (OC), small cell lung cancer (SCLC), and pancreatic cancer, and has been correlated to poor prognosis in the diseases. These malignant pathological profiles make CDK7 a pivotal target for the development of novel cancer therapy.
Furthermore, our results showed that TY-2699a demonstrated robust antitumor activity in acquired resistance to CDK 4/6 inhibitor breast cancer in vivo models, which suggests that TY-2699a is a potential treatment for patients who have received prior CDK4/6 inhibitor treatment and acquired drug-resistant.
