TYK Medicine announced that its independently developed next-generation oral, highly potent, and highly selective small-molecule CDK7 inhibitor, TY-2699a, has received official approval from the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) to conduct clinical trials for the treatment of advanced solid tumors in combination with different regimens. Previously, TY-2699a as a monotherapy had already received Study May Proceed Letters from both the CDE and the U.S. Food and Drug Administration (FDA) (IND 169813). Currently, there are no approved CDK7 inhibitors on the global market, and drugs targeting this pathway hold significant clinical potential.

About TY-2699a

TY-2699a is an independently developed oral, highly potent, and highly selective small-molecule CDK7 inhibitor by Zhejiang TYK Medicine Co., Ltd. The combination therapy is intended for the treatment of various advanced solid tumors, including breast cancer, pancreatic cancer, and head and neck squamous cell carcinoma. Phase I clinical trial results indicate that TY-2699a as a monotherapy has a low overall grade of adverse reactions, which are reversible and manageable. The vast majority of adverse events observed were Grade 1-2, consistent with preclinical in vitro and in vivo pharmacodynamic studies, which showed that TY-2699a selectively inhibits cancer cell growth without affecting normal cells at non-sensitive doses. This suggests good tolerability and safety. Additionally, TY-2699a monotherapy has demonstrated preliminary efficacy in some solid tumors. These clinical findings provide a solid foundation for further combination therapy studies.

About CDK7 Combination Therapy

Mechanism of Action in Combination with Fulvestrant or Oral SERD (Selective Estrogen Receptor Degraders) for Breast Cancer Treatment

In vivo studies have shown that treatment with a CDK7 inhibitor alone prevents the phosphorylation of estrogen receptor (ER) at serine 118, leading to upregulation of ER expression and activation of the ER signaling pathway. When a CDK7 inhibitor is combined with fulvestrant, the growth of ER-positive breast cancer tumors is significantly inhibited. Furthermore, RB-deficient and ER-mutant T47D Palbociclib-resistant cells have demonstrated high sensitivity to CDK7 inhibitors. Similar findings have been observed with other CDK7 inhibitors and have been supported by recent high-quality research reports. Additionally, the combination of CDK7 inhibitors with oral SERDs represents a promising direction for the treatment of ER-positive breast cancer.

Mechanism of Action in Combination with Gemcitabine and Nab-Paclitaxel for Chemotherapy

Nab-paclitaxel enhances the stability of gemcitabine by inhibiting cytidine deaminase, the key metabolic enzyme of gemcitabine. Additionally, in pancreatic cancer, high CDK7 expression hinders apoptosis induced by the combination of nab-paclitaxel and gemcitabine. CDK7 inhibition induces cell cycle arrest, apoptosis, and DNA damage through the STAT3-MCL1-CHK1 signaling axis. Therefore, targeting CDK7 can significantly enhance the efficacy of nab-paclitaxel and gemcitabine combination therapy.

Mechanism of Action in Combination with PD-1 Antibodies

Preclinical studies conducted by our company have shown that treatment with the CDK7 inhibitor TY-2699a in FaDu and Cal-27 cell lines activates the immune system and triggers an immune stress response. The selective CDK7 inhibitor YKL-5-124, when combined with anti-PD-1 therapy, has provided significant survival benefits in multiple aggressive SCLC mouse models, supporting a novel combination approach involving CDK7 inhibitors and immunotherapy. In NSCLC patients, the CDK7 inhibitor THZ1 has been shown to enhance the efficacy of PD-1 antibody immunotherapy, a mechanism associated with the p38α/MYC/PD-L1 pathway. Additionally, a preclinical-stage CDK7 inhibitor, THZ1, has been observed to induce significant changes in downstream genes related to therapeutic efficacy when co-cultured with nasopharyngeal carcinoma cells.