TP-1287, AN ORAL PRODRUG OF THE CYCLIN-DEPENDENT KINASE-9 INHIBITOR ALVOCIDIB
Author(s): ,
Wontak Kim
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Katherine Soh
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Ye Sol Lee
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Peter Peterson
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Kyle Maugham
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Clifford Whatcott
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Steven Weitman
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Steven Warner
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
David Bearss
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
Adam Siddiqui-Jain
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
(Abstract release date: May 19, 2016) EHA Learning Center. Whatcott C. Jun 9, 2016; 132440
Dr. Clifford Whatcott
Dr. Clifford Whatcott

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Abstract
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Abstract: E891

Type: Eposter Presentation

Background
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 protein such as MCL-1. Alvocidib, used in combination with cytarabine and mitoxantrone, is currently in a Phase II clinical trial in younger relapsed/refractory acute myeloid leukemia (AML) patients to evaluate the utility of a patient selection biomarker, dependent on MCL-1. Patients with AML that have a high dependence on MCL-1 are considered more likely to benefit from the alvocidib-containing regimen. Alvocidib is currently delivered by intravenous infusion which, although an effective delivery strategy, does not allow for chronic dosing and scheduling. An oral form or formulation of alvocidib could greatly expand the utility of the drug in combination with other targeted agents by allowing for more prolonged exposure. Alvocidib is highly permeable in CACO-2 monolayers and is soluble at acidic pH’s but solubility is strikingly reduced at neutral or basic conditions, which might hamper the development of an oral formulation.

Aims
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 planned to investigate the efficacy of an orally delivered phosphate prodrug using various treatment schedules in AML mouse xenograft models.

Methods
We synthesized TP-1287, a phosphate prodrug of alvocidib, in three steps from the parent compound. The solubility of TP-1287, was determined at various pH’s, in water. Pharmacokinetic studies were conducted in mice and efficacy was evaluated in AML xenograft mouse models using various dose levels and schedules. MCL-1 was evaluated as a pharmacodynamic biomarker in tumors from xenografted mice, following treatment with TP-1287.

Results
TP-1287 was found to be highly soluble under acidic, neutral, and basic conditions (1.52 mg/mL at pH 2.2; 1.81 mg/mL at pH 4.5; 9.48 mg/mL at pH 6.8 and 9.31 mg/mL at pH 8.7) compared to alvocidib (4.38 mg/mL at pH 2.2; 1.25 mg/mL at pH 4.5; 0.02 mg/mL at pH 6.8 and 0.02 mg/mL at pH 8.7). Pharmacokinetics studies in mice showed that TP-1287 was efficiently converted to the parent alvocidib (Cmax = 1922.7 ng/ml, t1/2 = 4.4 hr) with high oral bioavailability (%F > 100%, compared to intravenous alvocidib). TP-1287 demonstrated significant anti-tumor efficacy in an AML mouse xenograft model and produced a more than two-fold inhibition of the pharmacodynamic biomarker MCL-1 in xenografted tumors, demonstrating a wide, 75-fold therapeutic dosing window.

Conclusion
The phosphate prodrug of alvocidib, TP-1287, is highly soluble over a broader pH range than alvocidib and is efficiently metabolized to the parent compound in vivo. 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.

Session topic: E-poster

Keyword(s): BCL2, Mcl-1
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