Discovery of Kinase Spectrum Selective Macrocycle (16E)-14-Methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a Potent Inhibitor of Cyclin Dependent Kinases (CDKs), Janus Kinase 2 (JAK2), and Fms-like Tyrosine Kinase-3 (FLT3) for the Treatment of Cancer

Abstract

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53-dependent mechanism

“…To date, several small-molecule inhibitors have been designed to specifically target the MEK5/ERK5 pathway [26, 27, 48]. Equally important, TG02, a new oral pyrimidine-based multikinase inhibitor [49, 50], is also known to directly block ERK5 activity [51]. In fact, this promising antitumor agent is currently undergoing phase I trials in leukemia and multiple myeloma patients, providing the first clues to the benefits of targeting the MEK5/ERK5 cascade in clinical practice, and encouraging other ERK5-specific inhibitors such as XMD8-92 to progress into clinical evaluation.…”

Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation

“…41 Consequently, at least 75 clinical trials have been conducted in various cancer indications since 2000, using four different FTIs, namely tipifarnib, lonafarnib, BMS-214662 and L-778123. 42 However, most of these clinical trials have not been successful. For example, no significant survival gains were observed in patients with advanced solid cancers 43 or acute myeloid leukemia.…”

Oncogenic signaling of MEK5-ERK5

“…TG02, an oral pyrimidine-based multi-kinase inhibitor, blocks CDKs 1, 2, 3, 5, and 9 with IC 50 values below 10 nM in addition to janus kinase 2 (JAK2), p38δ, and ERK5 with IC 50 values of 19, 56, and 43 nM, respectively [37–39]. The pharmacokinetic profile showed drug levels retained in tumors were above the IC 50 for 8 and 24 hours after a single oral dose of 30 or 60 mg/kg, respectively [38].…”