Preclinical Development of TW01 Analogues as Potential Antitumor Therapeutic Agents

Background: TW01 analogues, with broad spectrum of antitumor activities on 60 human cancer cell lines (IC50 10-7~10-8M) and anti-angiogenesis activities。The lead TW01 exhibited in vivo antitumor activities in mice bearing HA22T human hepatoma or A549 human non-small cell lung cancer (ILS ＞30). TW01 was characterized by (1) inhibition on 18 cancer-related serine/threonine kinases (IC50 1.73 μM/PKBa/Akt1, 2.32 μM/Fyn, 1.4 μM/Erk & 11.1 μM/MEK), PI 3 kinases,abl tyrosine kinase (0.78 μM) and tyrosine phosphatase (1 ~ 0.1 μM); (2) higher inhibitory activitity than taxol on drug-resistant cancer cell lines; (3) mechanism of action different from taxol by inhibiting microtubule polymerization; and (4) a wide safety margin as screened on 136 proteins including receptors, transporters and 15 CYP450 metabolic enzymes. Unfortunately, poor physico-chemical property rendered TW01 difficult to be formulated to achieve a satisfactory systemic bioavailability. Chemical modification was thus conducted and lead to TW01001 and TW01002 with systemic bioavailability (F) improved up to 230 and 343 folds, respectively, with satisfactory half life (t1/2 9.12±5.86 & 15.5±12.57 hr, respectively). Both analogues demonstrated (1) in vovo anti-angiogenesis activities 10 times higher than that of TW01. TW01001 (20 mg/kg) exhibited moderate antitumor activity in mice bearing human HT29 colon cancer in a preliminary animal study (%TGD were 31%/10 mg/kg and 56%/20 mg/kg in comparison to 76% for taxol/15 mg/kg). However, MTD assay indicated that this compound showed higher safety profile than taxol. In summary, TW01, TW01001 and TW01002 are considered leads for further development at this drug discovery stage. Purpose: Formulation and chemical modification toward PD/PK optimization of the leads will be conducted. Method: We propose here a two year project to conduct preclinical development of TW01 leads in following aspects: (1) pre-formulation design for optimizing physico-chemical properties of the leads; (2) synthesis of soft or prodrugs in order to improve the physico-chemical properties of the leads; (3) PK determination on optimized formula; (4) provide pre-formulated leads for co-investigator to complete studies on at least three different in vivo rat tumor models for efficacy evaluation. Anticipated results: Drug candidate(s) will be generated, upon critical evaluation on the outcome after PD/PK optimization, for further development toward clinical studies.

Project ID:PD9607-0177
External Project ID:NSC96-2323-B038-003