Abstract LB_C13: Development of BLX-3030, a potent, selective, orally available CDK9i shows promise in Pancreatic Ductal Adenocarcinoma (PDAC) models
Authors: Medley Kyle , Li Zhaoliang , Lin Chenyu , Barrera-Millan Yesenia , Kelley Lynne , Han Haiyong , Vankayalapati Hariprasad , Bearss David J 
Published: December 2023

Abstract
Background: CDK9 (cyclin-dependent kinase 9), is a Ser/Thr kinase that plays a crucial role in regulating gene expression. It is a component of the P-TEFb complex, which controls transcription elongation by phosphorylating RNA polymerase II. Dysregulated CDK9 has been linked to cancer progression. Pharmacological CDK9 inhibition has recently emerged as a novel and promising approach for cancer therapy, particularly in exocrine pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNETs). PDAC and PNETs are cancer entities with a dismal prognosis, owing mainly to their resistance to chemo, radiation, and immunotherapies. Dysregulation of CDK9 activity can lead to uncontrolled cell cycle progression and tumor formation. Given the role of CDK9 in promoting PDACs progression, targeting this kinase has emerged as a potential therapeutic strategy for PDACs and PNETs where our late-breaking results of BLX-3030 demonstrated efficacy in pre-clinical tumor models.
Materials and Methods: Our proprietary MolecuLernTM fragment-based design platform, in vitro cellular efficacies as a single agent or combination, FACS/apoptosis, cell migration, live-cell imaging, and immunofluorescence assays. Top compounds were evaluated for 7-day tox, PK, selectivity, Nano BRET, ADME-Tox, in vitro safety, hERG, P450, SafetyScreen44 panel, LDH-Glo assay, and KINOMEscan for selectivity.
Results: Utilizing a CDK9-refined crystal structure and the MolecuLernTM, we identified novel, reversible, ATP-competitive inhibitors that exhibited potent activity in MYC-expressing pancreatic cancer cells in vitro. BLX-3030, elected from over 90 analogs demonstrated potent activity with an IC50 of 4.2 nM in inhibiting CDK9. CDKs family selectivity and target engagement NanoBRET assay results show the BLX-3030 selectivity and its on-target potency with an IC50 of 24.3 nM. BLX-3030 potently inhibited the growth of pancreatic cancer cells with IC50s ranging from 133 nM to 508 nM in 10 different cell lines. Furthermore, BLX-3030 and its analogs showed excellent PK properties in mice, rats, and dogs with an oral bioavailability of 28%, 38%, and 83%, respectively. BLX-3030 has a low clearance and &gt;3 hours half-life in rodents and canine species. The effect of BLX-3030 in vivo PDAC models including ex vivo results for the levels of CDK9, pCDK9, c-MYC, and cleaved Caspase 3 in tumor tissues will be discussed. Based on these pre-clinical results, BLX-3030 was nominated as a candidate with additional efficacy and safety data supporting IND-enabling studies
Conclusion: In summary, BLX-3030 is a potent CDK9i that displayed potent antitumor activity in pancreatic cancer models, with its promising safety, PK, and developable characteristics leading us to select and nominate as clinical candidates. Our late-breaking pre-clinical results from our in vivo study in pancreatic cancer tumor models, including 7-day safety, tolerability, and toxicokineCDK9tic results received are supportive for our planned ND enabling studies and future clinical trials will be presented.
Citation Format: Kyle Medley, Zhaoliang Li, Chenyu Lin, Yesenia Barrera-Millan, Lynne Kelley, Haiyong Han, Hariprasad Vankayalapati, David J Bearss. Development of BLX-3030, a potent, selective, orally available CDK9i shows promise in Pancreatic Ductal Adenocarcinoma (PDAC) models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C13.