Abstract 1254: Preclinical studies with TGN-1062, a selective and reversible small molecule inhibitor of CDK7
Authors: Rodriguez del Villar Ryan L. , Thode Trason G. , Weston Alexis , Ng Serina , Soldi Raffaella , Kaadige Mohan , Kasibhatla Srinivas , Chung Vincent , Chao Joseph , Von Hoff Daniel D. , Sharma Sunil 
Published: July 2021

Abstract
Purpose: Cancer causing mutations promote unchecked cell cycle progression and altered gene expression to drive tumor growth. Cyclin-dependent Kinase 7 (CDK7) is a critical player in tumorigenesis not only due to its role in cell cycle regulation through the phosphorylation of other CDKs, but also as part of the TFIIH complex where it stimulates transcription via phosphorylation of RNA Polymerase II. It is also known to be associated with Super Enhancers (SEs). When tumor cells acquire SEs at oncogenic driver genes, such as BCL2, GFI1, and MYC, it can lead to the activation of their expression as well as induce transcriptional reprogramming. When CDK7 is overexpressed, it is associated with poor clinical outcomes (AML, breast, ovarian, pancreatic, SCLC, etc.). Inhibition of CDK7 is a promising strategy for abating uncontrolled expression of these oncogenic genes. We have developed TGN-1062, designed to competitively bind the CDK7 catalytic ATP pocket. TGN-1062 is a potent, selective, and reversible inhibitor of CDK7 with desirable drug-like properties. Here, we have further validated our candidate TGN-1062 as a potent inhibitor of CDK7 with efficacy in multiple murine in vivo models.
Methods: In vivo efficacy studies were conducted in nude mice engrafted with A2780, HCT116, or MV4-11 tumor cells and treatment with TGN-1062. Tumors were measured to determine tumor growth inhibition (TGI) and correlating drug accumulation were measured in both tumors and plasma using mass spectrometry. Immunohistochemistry (IHC) was performed on tumors to determine changes in cleaved Caspase, cMYC, Ki67, and RNA Pol II. NanoBRET assay was used to demonstrate inhibition of CDK7 activity in living cells. Changes in MCL-1, MYC, cleaved PARP, and RNA Pol II phosphorylation was demonstrated by Western blotting from TGN-1062 treated A2780 and MV4-11 cellular lysates. Drug combinations with TGN-1062 were performed in multiple cancer cell lines.
Results: TGN-1062 inhibits CDK7 in the NanoBRET cellular assay with low nanomolar potency (&lt; 0.508 nM) and induces a dose dependent change in biomarkers shown via Western blotting in ovarian and AML cancer cell lines. TGN-1062 showed a TGI of 60% at the total daily dose of 50 mg/kg PO in an ovarian model (A2780) and 50% in the colorectal model (HCT116). Additionally, TGN-1062 had a TGI of 75% at the total daily dose of 50 mg/kg PO and 80% at the total daily dose of 100 mg/kg PO in the AML (MV4-11) xenograft model. Drug accumulation, biomarker analysis, and IHC from murine tumors, show that TGN-1062 treatment decreases RNA POL II phosphorylation and MYC expression, and increases apoptosis markers.
Conclusion: TGN-1062 is a novel, selective, and reversible inhibitor of CDK7 and has significant antitumor activity in vivo. TGN-1062 is a potent CDK7 inhibitor with potential for clinical development.
Citation Format: Ryan L. Rodriguez del Villar, Trason G. Thode, Alexis Weston, Serina Ng, Raffaella Soldi, Mohan Kaadige, Srinivas Kasibhatla, Vincent Chung, Joseph Chao, Daniel D. Von Hoff, Sunil Sharma. Preclinical studies with TGN-1062, a selective and reversible small molecule inhibitor of CDK7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1254.