Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development.

Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).

Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor.

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).

Hot water-promoted S(N)1 solvolysis reactions of allylic and benzylic alcohols.

During the studies of hydrolysis of epoxides in water, we found that the hydrolysis of (-)-α-pinene oxide at 20 °C gave enantiomerically pure trans-(-)-sobrerol, whereas the same reaction in water heated at reflux unexpectedly gave a racemic mixture of trans- and cis-sobrerol (trans/cis = 6:4). We have examined this remarkable difference in detail and found that hot water, whose behavior is quite different compared with room- or high-temperature water, could promote S(N)1 solvolysis reactions of allylic alcohols and thus caused the racemization of trans-(-)-sobrerol. The effect of reaction temperature, the addition of organic co-solvent, and the concentration of the solute on the rate of the racemization of trans-(-)-sobrerol were further examined to understand the role that hot water played in the reaction. It was proposed that the catalytic effects of hot water are owing to its mild acidic characteristic, thermal activation, high ionizing power, and better solubility of organic reactant. Further investigation showed that the racemization of other chiral allylic/benzylic alcohols could efficiently proceed in hot water.

Hot water-promoted ring-opening of epoxides and aziridines by water and other nucleopliles.

Effective hydrolysis of epoxides and aziridines was conducted by heating them in water at 60 or 100 degrees C. Other types of nucleophile such as amines, sodium azide, and thiophenol could also efficiently open epoxides and aziridines in hot water. It was proposed that hot water acted as a modest acid catalyst, reactant, and solvent in the hydrolysis reactions.