kx-01 and Neoplasms

Src kinase is central to tumor cell proliferation, apoptosis, and metastasis. KX2-391 is a synthetic, orally bioavailable small molecule inhibitor of Src tyrosine kinase (TK) signaling and tubulin polymerization. This compound is distinct from other Src kinase inhibitors by targeting the peptide substrate rather than the ATP binding site; the binding site on hetero-dimeric tubulin is novel and distinct from the taxanes and other known tubulin inhibitors.. This multicenter Phase I trial utilized a 4 + 2 study design to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of KX2-391 in patients with refractory solid tumors.. Forty-four (44) patients (18 M, 26 F; median age, 59) were enrolled in 9 dose cohorts. Dose-limiting toxicities, all reversible within 7 days, occurred in 7 patients and consisted of elevated AST (n = 4), ALT (n = 2), neutropenia (n = 1), thrombocytopenia (n = 1), failure to thrive (n = 1) and anorexia (n = 1). The MTD is 40 mg BID continuously. Eleven patients had stable disease for ≥ 4 months, including patients with ovarian, carcinoid, papillary thyroid, prostate, pancreas and head and neck cancer. Patients with prostate and pancreatic cancer also had significant biomarker decreases (PSA, 205 ng/mL to 39 ng/mL; CA19-9, 38,838 U/mL to 267 U/mL). The ovarian cancer patient has had stable disease > 12 months. KX2-391 was orally available, rapidly absorbed, and exposure was proportional to dose across the range investigated.. KX2-391 has a favorable pharmacokinetic profile, is well tolerated, demonstrates preliminary evidence of biologic activity, and warrants further evaluation in Phase II trials.

Topics: Acetamides; Adenosine Triphosphate; Binding Sites; Demography; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Neoplasm Staging; Neoplasms; Protein Kinase Inhibitors; Pyridines; src-Family Kinases; Substrate Specificity

Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of β-tubulin and its morpholine group lies close to α-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with α-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives,

Topics: Acetamides; Animals; Antineoplastic Agents; Cattle; Cell Line, Tumor; Chickens; Crystallography, X-Ray; Drug Design; Female; G2 Phase Cell Cycle Checkpoints; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Morpholines; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Pyridines; Rats, Sprague-Dawley; Signal Transduction; src-Family Kinases; Structure-Activity Relationship; Tubulin; Tubulin Modulators