Abstract 5133: TP-1287, an oral prodrug of the cyclin-dependent kinase-9 inhibitor alvocidib

Abstract

Alvocidib is a potent inhibitor of cyclin-dependent kinase-9 (CDK9) and induces apoptosis in cancer cells by reducing the expression of short-lived, anti-apoptotic proteins such as MCL-1. Alvocidib, as a part of a sequential combination regimen with cytarabine and mitoxantrone (ACM), is currently in a Phase II clinical trial in relapsed/refractory acute myeloid leukemia (AML). Patients with AML that have a high dependence on MCL-1 are considered more likely to benefit from the alvocidib-containing regimen. MCL-1 has emerged as a key protein in drug resistance of multiple solid tumor types including breast, prostate and lung cancers. The use of alvocidib in clinical settings beyond the ACM regimen is somewhat limited by the current intravenous route of administration. An orally administered form of alvocidib would allow prolonged repression of MCL-1 through chronic dosing and scheduling. Alvocidib itself is highly permeable in CACO-2 monolayers and is soluble at acidic pHs but solubility is strikingly reduced at neutral or basic conditions, which could hamper the development of an oral formulation. We hypothesized that a phosphate prodrug of alvocidib would improve solubility under neutral or basic conditions and enable the efficient systemic delivery of alvocidib via oral administration. We synthesized a phosphate prodrug of alvocidib, TP-1287, in three steps from the parent compound. The solubility of TP-1287, was determined at various pH levels. It was found to be highly soluble under acidic, neutral, and basic conditions (1.5 mg/mL at pH 2.2; 1.8 mg/mL at pH 4.5; 9.5 mg/mL at pH 6.8 and 9.3 mg/mL at pH 8.7) compared to alvocidib (4.4 mg/mL at pH 2.2; 1.3 mg/mL at pH 4.5; 0.02 mg/mL at pH 6.8 and 0.02 mg/mL at pH 8.7). Pharmacokinetic studies were conducted in mice in which TP-1287 was efficiently converted to the parent alvocidib (Cmax = 1922.7 ng/ml, t1/2 = 4.4 hr) with high oral bioavailability (%F = 182.3, compared to intravenous alvocidib). Efficacy and pharmacodynamic studies (measuring MCL-1 expression levels), were evaluated in tumor xenograft models. TP-1287 demonstrated significant anti-tumor efficacy in the MV4-11 AML mouse xenograft model and produced as much as a 61.7% inhibition of the pharmacodynamic biomarker MCL-1 in xenografted tumors, demonstrating a wide, 75-fold therapeutic dosing window. In addition, TP-1287 strongly inhibited tumor growth, achieving 109.1% tumor growth inhibition (%TGI) at the 7.5 mg/kg dose level. TP-1287 is highly soluble over a broader pH range than alvocidib and is efficiently metabolized to the parent compound in vivo, following oral administration. Tumor xenograft models and pharmacodynamic studies indicate that oral delivery of TP-1287 is efficacious in mice. Based on these results, we anticipate moving TP-1287, as an orally delivered CDK9 inhibitor, into a forthcoming clinical trial directed towards solid tumors vulnerable to the suppression of MCL-1. Citation Format: Wontak Kim, Hillary Haws, Peter Peterson, Clifford J. Whatcott, Steven Weitman, Steven L. Warner, David J. Bearss, Adam Siddiqui-Jain. TP-1287, an oral prodrug of the cyclin-dependent kinase-9 inhibitor alvocidib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5133. doi:10.1158/1538-7445.AM2017-5133

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

“…There is an open clinical question as to whether transcriptional inhibitors can exploit this vulnerability with acceptable toxicity profiles. Currently, several transcriptional CDK inhibitors, including CDK9-preferring inhibitors, are either in clinical trials or in late-stage preclinical development (Bisi et al, 2017;Cidado et al, 2020;Clark et al, 2017;Goh et al, 2012;Hu et al, 2019;Kawakami et al, 2019;Kim et al, 2017;L€ ucking et al, 2017). Many of these drugs have activity against multiple CDKs, making it difficult to fully assess the specific contribution of CDK9 inhibition to efficacy.…”

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

“…This phosphate prodrug has an improved solubility under neutral or basic conditions allowing oral administration of the drug. Pharmacodynamic and efficacy studies in acute myeloid leukemia ( Kim et al., 2017 ) and prostate cancer ( Forostyan et al., 2019 ) xenografted models, showed that orally delivered TP-1287 is efficiently metabolized and enhances tumor regression in vivo . A phase I study using oral TP-1287 is actively recruiting to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) in patients with advanced metastatic or progressive solid tumors who are refractory to established therapy ( Table 1 ).…”

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

“…208 TP-1287 has shown in vivo efficacy in the MV-4-11 AML mouse xenograft model with 109% TGI at 7.5 mg/kg, PO. 208 Tolero Pharmaceuticals, Inc., is evaluating TP-1287 in phase I clinical trial in patients with advanced solid tumors. 209 P276-00 (riviciclib, 72) is the second candidate that emerged from this skeleton 210 211 In its phase II clinical trial in 13 patients with relapsed or refractory MCL, two patients had stable disease at the end of the P276-00 treatment, whereas 11 patients experienced treatment-related AE's.…”

“…Currently, it is being investigated in two trials in combination with venetoclax for AML, 206 and in combination with decitabine for MDS 207 . Tolero pharmaceuticals discovered an orally active TP‐1287 ( 71 ), a phosphate prodrug of flavopiridol which gets enzymatically cleaved to its active metabolite flavopiridol at the tumor site 208 . TP‐1287 has shown in vivo efficacy in the MV‐4‐11 AML mouse xenograft model with 109% TGI at 7.5 mg/kg, PO 208 .…”

“…Tolero pharmaceuticals discovered an orally active TP‐1287 ( 71 ), a phosphate prodrug of flavopiridol which gets enzymatically cleaved to its active metabolite flavopiridol at the tumor site 208 . TP‐1287 has shown in vivo efficacy in the MV‐4‐11 AML mouse xenograft model with 109% TGI at 7.5 mg/kg, PO 208 . Tolero Pharmaceuticals, Inc., is evaluating TP‐1287 in phase I clinical trial in patients with advanced solid tumors 209 .…”