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1.
Invest New Drugs ; 40(4): 773-781, 2022 08.
Article in English | MEDLINE | ID: mdl-35579731

ABSTRACT

Poor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. This multi-center phase Ib open-label safety and activity study involved elderly patients with relapsed or refractory AML, or who declined standard chemotherapy. Twenty-four patients averaging 74 years of age were enrolled. The majority previously received hypomethylating agents. Five doses were tested: 40 mg (n = 1), 80 mg (n = 2), 120 mg (n = 8), 140 mg (n = 12), and 160 mg (n = 1). Seven patients were treated for 12 days or less, nine for 15-29 days, five for 33-58 days, and three for 77-165 days. One patient receiving 120 mg for 165 days had reduced splenomegaly and survived 373 days. Another had no evidence of disease progression for 154 days. One patient receiving 160 mg for 12 days remained treatment-free for about 18 months. Dose-limiting toxicities occurred in eight patients at: 120 mg (transaminitis, hyperbilirubinemia), 140 mg (mucositis, allergic reaction, transaminitis, acute kidney injury), and 160 mg (mucositis). The maximum tolerated dose for KX2-391 was 120 mg once daily. KX2-391 bone marrow concentrations were approximately similar to plasma concentrations. This is the first study to evaluate the safety of KX2-391 in elderly patients with AML. Further studies are warranted, including alternative dosing phase I trials evaluating shorter courses at higher doses and phase II trials. (Clinical Trial Registration:The study was registered at ClinicalTrials.gov: NCT01397799 (July 20, 2011)).


Subject(s)
Leukemia, Myeloid, Acute , Mucositis , Acetamides , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Maximum Tolerated Dose , Morpholines/therapeutic use , Mucositis/drug therapy , Pyridines
2.
J Neurooncol ; 140(3): 519-527, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30238350

ABSTRACT

PURPOSE: A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood-brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity. METHODS: KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma. RESULTS: In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture. CONCLUSIONS: The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.


Subject(s)
Acetamides/administration & dosage , Antineoplastic Agents/administration & dosage , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Morpholines/administration & dosage , Pyridines/administration & dosage , Tubulin Modulators/administration & dosage , src-Family Kinases/antagonists & inhibitors , Animals , Apoptosis , Blood-Brain Barrier/metabolism , Brain Neoplasms/drug therapy , Cell Cycle Checkpoints , Cell Line, Tumor , Disease Models, Animal , Glioblastoma/drug therapy , Humans , Mice, Inbred C57BL , Phosphorylation , Protein Kinase Inhibitors/administration & dosage
3.
J Med Chem ; 61(11): 4704-4719, 2018 06 14.
Article in English | MEDLINE | ID: mdl-29617135

ABSTRACT

The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA.


Subject(s)
Acetamides/pharmacology , Drug Discovery , Morpholines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Tubulin Modulators/pharmacology , src-Family Kinases/antagonists & inhibitors , Acetamides/metabolism , Amino Acid Sequence , Catalytic Domain , Cell Line, Tumor , Humans , Molecular Docking Simulation , Morpholines/metabolism , Protein Kinase Inhibitors/metabolism , Pyridines/metabolism , Signal Transduction/drug effects , Tubulin Modulators/metabolism , src-Family Kinases/chemistry , src-Family Kinases/metabolism
4.
Bioorg Med Chem Lett ; 26(16): 3850-4, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27445170

ABSTRACT

Ligand-protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host. Upon binding, ligand functional groups can act synergistically (positive cooperativity) to improve the overall ligand binding affinity beyond what would be expected from their individual contributions. In this study, using thrombin as a protein model system, we evaluated the effect of the bioisosteric replacement of a carbonyl functionality with a sulphonyl functionality on positive cooperativity between their H-bonds with thrombin and hydrophobic binding in the adjacent S3 pocket. The positive cooperativity observed was greatly reduced when replacing the carbonyl group with a sulphonyl group. Evaluating how bioisosteric replacements affect cooperativity is important for making better informed ligand optimization SAR decisions.


Subject(s)
Antithrombins/chemistry , Thrombin/antagonists & inhibitors , Antithrombins/metabolism , Binding Sites , Catalytic Domain , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Docking Simulation , Protein Binding , Structure-Activity Relationship , Sulfur Dioxide/chemistry , Thermodynamics , Thrombin/metabolism
5.
Eur J Med Chem ; 96: 405-24, 2015.
Article in English | MEDLINE | ID: mdl-25912673

ABSTRACT

One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positive cooperativity between an H-bond accepting carbonyl functionality and the adjacent P3 hydrophobic side chain. Adding an H-bond donating amine adjacent to the P3 hydrophobic side chain further increases this positive cooperativity thereby improving the Ki by as much as 546-fold. In contrast, adding an amidine multiple H-bond/salt bridge group in the distal S1 pocket does not affect this cooperativity. An analysis of the crystallographic B-factors of the ligand groups inside the binding site indicates that the strong cooperativity is mainly due to a significant mutual reduction in the residual mobility of the hydrophobic side chain and the H-bonding functionalities that is absent when the separation distance is large. This type of cooperativity is important to encode in binding affinity prediction software, and to consider in SAR studies.


Subject(s)
Antithrombins/pharmacology , Thrombin/antagonists & inhibitors , Antithrombins/chemistry , Binding Sites/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thrombin/metabolism
6.
Clin Cancer Res ; 19(23): 6532-43, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24100628

ABSTRACT

PURPOSE: To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. EXPERIMENTAL DESIGN: The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. RESULTS: In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2-M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. CONCLUSION: Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.


Subject(s)
Acetamides/pharmacology , Adenocarcinoma, Mucinous/drug therapy , Antineoplastic Agents/pharmacology , Ovarian Neoplasms/drug therapy , Pyridines/pharmacology , Tubulin Modulators/pharmacology , src-Family Kinases/antagonists & inhibitors , Acetamides/therapeutic use , Adenocarcinoma, Mucinous/metabolism , Adenocarcinoma, Mucinous/pathology , Animals , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Cycle , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Synergism , Female , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Microtubules/metabolism , Morpholines , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Oxaliplatin , PTEN Phosphohydrolase/metabolism , Protein Multimerization , Pyridines/therapeutic use , Tubulin Modulators/therapeutic use , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , src-Family Kinases/metabolism
7.
Invest New Drugs ; 31(4): 967-73, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23361621

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: KX2-391 has a favorable pharmacokinetic profile, is well tolerated, demonstrates preliminary evidence of biologic activity, and warrants further evaluation in Phase II trials.


Subject(s)
Acetamides/therapeutic use , Adenosine Triphosphate/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , src-Family Kinases/antagonists & inhibitors , Acetamides/adverse effects , Acetamides/pharmacokinetics , Acetamides/pharmacology , Binding Sites , Demography , Dose-Response Relationship, Drug , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Morpholines , Neoplasm Staging , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyridines/pharmacology , Substrate Specificity/drug effects , src-Family Kinases/metabolism
8.
Cancer Chemother Pharmacol ; 71(4): 883-92, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23314737

ABSTRACT

PURPOSE: KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC). METHODS: We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin]. RESULTS: The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥ 30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥ 5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C max was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation. CONCLUSION: KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C max of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.


Subject(s)
Acetamides/therapeutic use , Bone Neoplasms/secondary , Prostatic Neoplasms/drug therapy , Pyridines/therapeutic use , Tubulin Modulators/therapeutic use , src-Family Kinases/antagonists & inhibitors , Acetamides/adverse effects , Acetamides/pharmacokinetics , Administration, Oral , Aged , Aged, 80 and over , Bone and Bones/metabolism , Humans , Male , Middle Aged , Morpholines , Neoplastic Cells, Circulating/drug effects , Orchiectomy , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Pyridines/adverse effects , Pyridines/pharmacokinetics , Tubulin Modulators/adverse effects , Tubulin Modulators/pharmacokinetics
9.
Eur J Med Chem ; 46(10): 4853-8, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21852023

ABSTRACT

KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI(50) values of 1.34 µM and 2.30 µM in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. 4-Fluorobenzylthiazolyl derivative 8b exhibited 64-71% inhibition in the cell proliferation of BT-20 and CCRF cells at concentration of 50 µM.


Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , src-Family Kinases/antagonists & inhibitors , Acetamides/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Female , Humans , Inhibitory Concentration 50 , Leukemia/drug therapy , Mice , Morpholines , NIH 3T3 Cells , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology , src-Family Kinases/metabolism
10.
J Med Chem ; 53(5): 2126-35, 2010 Mar 11.
Article in English | MEDLINE | ID: mdl-20148533

ABSTRACT

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per A(2) of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per A(2) demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.


Subject(s)
Serine Proteinase Inhibitors/chemistry , Thrombin/antagonists & inhibitors , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Protein Binding/physiology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thermodynamics , Thrombin/metabolism
12.
Bioorg Med Chem Lett ; 14(15): 3875-9, 2004 Aug 02.
Article in English | MEDLINE | ID: mdl-15225688

ABSTRACT

Structure-based-design studies, with the crystal structure of the HOXB1-PBX1/DNA transcription factor complex, were used to identify 1,4-disubstituted naphthalenes as potential antagonists. An initial library of 32 analogs was synthesized, two of which were found to be more potent than the reported activity for a 12 amino acid peptide antagonist. Antagonists were also identified of the related BRN1/DNA and BRN2/DNA transcription factor complexes indicating that a 1,4-disubstituted naphthalene may be a privileged scaffold for preparing screening libraries targeting this family of transcription factor complexes.


Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Homeodomain Proteins/antagonists & inhibitors , Naphthalenes/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Transcription Factors/antagonists & inhibitors , Crystallography, X-Ray , DNA/antagonists & inhibitors , DNA-Binding Proteins/chemistry , Homeodomain Proteins/chemistry , Humans , Kinetics , Models, Molecular , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Pre-B-Cell Leukemia Transcription Factor 1 , Proto-Oncogene Proteins/chemistry
13.
J Org Chem ; 61(5): 1872-1874, 1996 Mar 08.
Article in English | MEDLINE | ID: mdl-11667067
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