Papers by kantharaj ethirajulu
Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetyla... more Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase (HDAC) inhibitor, and prediction of human pharmacokinetics
SARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is kn... more SARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is known about the mechanisms of action of these antibodies or their effective dosing windows. We report the discovery and development of SC31, a potent SARS-CoV-2 neutralizing IgG1 antibody, originally isolated from a convalescent patient at day 27 after the onset of symptoms. Neutralization occurs via a binding epitope that maps within the ACE2 interface of the SARS-CoV-2 Spike protein, conserved across all common circulating SARS-CoV-2 mutants. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, SC31 demonstrated potent survival benefit by dramatically reducing viral load concomitant with attenuated pro-inflammatory responses linked to severe systemic disease, such as IL-6. Comparison with a Fc-null LALA variant of SC31 demonstrated that optimal therapeutic efficacy of SC31 requires intact Fc-mediated effector functions that can further induce an IFNγ-driven anti-viral immune response. ...
Blood
588 The Janus kinase 2 (JAK2)/ signal transducers and activators of transcription (STAT) pathway ... more 588 The Janus kinase 2 (JAK2)/ signal transducers and activators of transcription (STAT) pathway plays an important role in the proliferation and pathogenesis of hematological malignancies. Somatic activating point mutations in the JAK2 gene has been reported in most myeloproliferative disorders (MPDs), but are rarely described in Hodgkin (HL) and non-Hodgkin lymphomas (NHL). JAK2 activation has been reported to be associated with mutation of the Suppressor of Cytokine Signaling (SOCS)-1 gene in HL and primary mediastinal large cell NHL, and in vitro inhibition of JAK2 demonstrated antiproliferative activity in a variety of lymphoma cell lines. With this background, we initiated a Phase-I study of the novel JAK2 small molecule inhibitor SB1518 in patients with relapsed HL and NHL. Patients and Methods: The primary objectives were to examine the safety and efficacy of SB1518 in this patient population. Patients were eligible if they had relapsed or refractory HL or NHL of any type (e...
Blood
3292 Background: SB939 is a novel orally bioavailable inhibitor of class 1, 2 and 4 histone deace... more 3292 Background: SB939 is a novel orally bioavailable inhibitor of class 1, 2 and 4 histone deacetylases. In human tumor cell lines SB939 inhibits proliferation and promotes apoptosis at an IC50 of 0.1 – 1.3mM. Antitumor activity has been demonstrated in xenograft models of AML (MV4-11) and B-cell lymphoma (Ramos), as well as solid tumors. A phase I, open label, dose escalation study in patients with advanced hematologic malignancies was conducted to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary efficacy of SB939. Methods: SB939 was administered orally every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle. Cohorts of patient were treated with escalating doses of SB939 starting from 10 mg. The MTD was defined as the lowest dose level with less than 2 DLTs. The recommended Phase 2 dose level was defined as one dose level below the MTD. PK and PD (Acetylated Histone 3 in PBMCs) samples were collected in the first...
Clinical and Translational Science
In the last decade, drug development has tackled substantial challenges to improve efficiency and... more In the last decade, drug development has tackled substantial challenges to improve efficiency and facilitate access to innovative medicines. Integrated clinical protocols and the investigation of targeted oncology drugs in healthy volunteers (HVs) have emerged as modalities with an increase in scope and complexity of early Accepted Article This article is protected by copyright. All rights reserved. clinical studies and First in Human studies (FIHs) in particular. However, limited work has been done to explore the impact of these two modalities, alone or in combination, on the scientific value and on the implementation of such articulated studies. We conducted a FIH study in HVs with an oncology targeted drug, a Mnk 1/2 small molecule inhibitor. In this article we describe results, advantages and limitations of an integrated clinical protocol with an oncology drug. We further discuss and indicate points to consider when designing and conducting similar scientifically and operationally demanding, FIH studies.
Journal of Clinical Oncology
2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiatio... more 2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, med...
Ash Annual Meeting Abstracts, Nov 20, 2009
Abstract 3905 Poster Board III-841 Mutation of Janus Associated Kinase 2 (JAK2) at amino acid 617... more Abstract 3905 Poster Board III-841 Mutation of Janus Associated Kinase 2 (JAK2) at amino acid 617 and the resulting constitutively active JAK2V617F enzyme has been linked to the pathogenesis of myeloproliferative neoplasms (MPN). Fms-like Kinase 3 (FLT3) is a receptor tyrosine kinase expressed by immature hematopoietic cells. FLT3 abnormalities are present in ∼30% of acute myelogenous leukemias (AML). SB1518 is a potent ATP-competitive inhibitor of both JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) that is selective for JAK2 inhibition compared to JAK1 and JAK3 (58 and 24 fold, respectively). It also potently inhibits FLT3 (IC50 = 22 nM) and its mutant D835Y (IC50 = 6 nM). SB1518 inhibits proliferation of human leukemia and lymphoma cell lines dependent on either JAK2 or FLT3 activation (IC50 =35-240 nM), and has antitumor activity in nude mouse models of FLT3- (MV4-11) or JAK2-dependent (BaF3-JAK2V617F) leukemia. Based on these encouraging data, SB1518 is being evaluated in subjects with acute and chronic myeloid diseases in a Phase I dose escalation study. Objectives of the trial are to determine the safety, tolerability and PK/PD profile of SB1518 when administered orally once daily continuously in 28-day cycles. Thirty-six patients have been enrolled to date and treated at 6 dose levels, from 100-600 mg daily: 31/36 myelofibrosis (MF), 5/36 AML. Median number of prior therapies was 2. At 600 mg, 3 of 6 patients experienced dose-limiting toxicity (GI symptoms requiring drug interruption). All 3 recovered and restarted SB1518 at a reduced dose. The most common related adverse events have been diarrhea 33% (4% Grade 3), nausea 13% (all Grade 1/2), and thrombocytopenia 4% (all Grade 3/4). Four deaths have occurred due to disease progression or intercurrent illness. To date, twenty-two patients remain on study and enrollment is on-going. Thirteen patients have been treated for ≥6 months and 3 ≥1 year. 21 MF patients are evaluable for response: 7/17 (41%) with palpable splenomegaly had a decrease in spleen size by physical exam of ≥ 35%, of which 4 (24%) had a decrease of ≥50%. SB1518 was rapidly absorbed with Tmax of 3-5 hours and mean elimination half-life of 2-3 days. There was no drug accumulation after repeated cycles of administration. Pharmacologically active levels were achieved at the starting dose level of 100 mg based on target efficacy biomarker assessment. Measurement of pSTAT3 and pSTAT5 in fixed whole blood and lysed peripheral blood mononuclear cells on the first day of dosing showed inhibition of pSTAT3 and pSTAT5 4-6 hours post dose at all dose levels. In conclusion, SB1518 was well tolerated at doses up to 500 mg daily in advanced patients with MF and AML, and shows promising clinical activity in MF patients with splenomegaly. Disclosures: Wood: S*BIO PTE LTD: Employment. Ethirajulu:S*BIO PTE LTD: Employment. Lowe:S*BIO PTE LTD: Consultancy. Zhu:S*BIO PTE LTD: Employment.
Journal of Medicinal Chemistry, Dec 1, 2005
Identification of metabolic biotransformations can significantly affect the drug discovery proces... more Identification of metabolic biotransformations can significantly affect the drug discovery process. Since bioavailability, activity, toxicity, distribution, and final elimination all depend on metabolic biotransformations, it would be extremely advantageous if this information could be produced early in the discovery phase. Once obtained, this information can help chemists to judge whether a potential candidate should be eliminated from the pipeline or modified to improve chemical stability or safety of new compounds. The use of in silico methods to predict the site of metabolism in phase I cytochrome-mediated reactions is a starting point in any metabolic pathway prediction. This paper presents a new method, specifically designed for chemists, that provides the cytochrome involved and the site of metabolism for any human cytochrome P450 (CYP) mediated reaction acting on new substrates. The methodology can be applied automatically to all the cytochromes for which 3D structure is known and can be used by chemists to detect positions that should be protected in order to avoid metabolic degradation or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early ADME-Tox assays (absorption, distribution, metabolism, and excretion toxicity assays), where drug safety and metabolic profile patterns must be evaluated as soon, and as early, as possible.
Current Protein & Peptide Science, 2015
He has published 52 scientific works and two chapters of books. He is director of four research p... more He has published 52 scientific works and two chapters of books. He is director of four research programs in chemometrics and food analysis in Argentina, as well as director of doctoral theses and fellows. In 2013, he has been awarded in 2013 with the XIII Edition of Agricultural Excellence Prize (Argentina).
Blood cancer journal, 2012
Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well t... more Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and t...
detectable changes in glycolysis that could serve as biomarkers of target suppression in human ca... more detectable changes in glycolysis that could serve as biomarkers of target suppression in human cancer cells. Methods: We used the MEK inhibitor CI-1040 and three human cancer cell lines, HCT116 (colorectal), SKMEL-28 and WM 266.4 (melanoma). Cells were treated with 20 mM of CI-1040 for 16 h and 24 h (HCT116) or with 1 mM of CI-1040 for 24 h (SKMEL-28 and WM 266.4). Post-treatment, 10 7-10 8 cells were extracted with dual phase extraction and 1 H MRS spectra of the water soluble metabolites were acquired on an 11.7 T Bruker Avance spectrometer. In addition, cell culture media from 16 h treatments with HCT116 cells were analysed. Levels of PERK and downstream targets cyclin D1 and pRB, were evaluated with Western blotting to confirm successful MEK signalling inhibition in response to treatment. Results: Exposure to CI-1040 led to a marked decrease of ERK phosphorylation as well as levels of cyclin D1 and pRB as shown by Western blotting. Post-treatment, 1 H MRS data revealed decreased intracellular lactate levels to 44±10% at 16 h (n = 3, P = 0.01) and 62±14% at 24 h (n = 2) in HCT116 cells. Intracellular lactate levels decreased to 45±18% in SKMEL-28 cells and to 45±2% in WM 266.4 cells at 24 h post-treatment (n = 2). Extracellular lactate levels were unchanged 16 h post-treatment in HCT116 cells. Conclusion: These results demonstrate that MEK inhibition leads to modulation of glycolysis in human colorectal cancer and melanoma cells. Our findings need to be evaluated further in vivo and by the use of additional MEK inhibitors, nevertheless they suggest a role for lactate as a potential non-invasive MRS biomarker of response to MEK targeted therapeutics.
Drug metabolism letters, Jan 18, 2015
The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and ... more The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~ 5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes. In vitro metabolism studies with mouse and human liver microsomes showed the presence of four major metabolites of Pacritinib -M1 (oxidation), M2 (dealkylation), M3 (oxidation), M4 (reduction). The in vitro and in vivo metabolic patterns observed in mice and humans were in good agreement. Qualitatively and quantitatively, none of the metabolites formed in vivo was > 10% of Pacritinib in mouse, dog and humans. Pacritinib showed systemic clearance of 8.0, 1.6, 1.6 l/h/kg, volume of distribution of 14.2, 7.9, 8.5 l/kg, t1/2 of 5.6, 6.0, 4.6 h, and oral bioavailability of 39, 10, and 24% in mouse, rat and dog, respectively. In radiolabeled ...
Leukemia, 2012
TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together... more TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.
Discovery of Kinase Spectrum Selective Macrocycle (16 E )-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 Ki... Journal of Medicinal Chemistry, 2012
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycl... more 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.
The Journal of Immunology, 2012
SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK fa... more SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.
Ejc Supplements - EJC SUPPL, 2009
such as proliferation or cell death (apoptosis). IHC is also widely used in basic research to und... more such as proliferation or cell death (apoptosis). IHC is also widely used in basic research to understand the distribution and localization of biomarkers and differentially expressed proteins in different parts of a biological tissue. Visualising an antibody-antigen interaction can be accomplished in a number of ways. In the most common instance, an antibody is conjugated to an enzyme, such as peroxidase, that can catalyse a colour-producing reaction. Alternatively, the antibody can also be tagged to a fluorophore, (immunofluorescence). Materials and Methods: In Cameroon, the above techniques are not available. We established a collaboration with a few laboratories in developed countries; mainly in Switzerland and France. Paraffin blocks of diagnosed cancers have been sent abroad since January 2000. Immunohistochemistry has been performed free of charge. Results: A series of 103 cancer patients was included in this study. There were 40 malignant lymphomas, 20 cases of early stage Kaposi's sarcoma, 20 soft tissue tumours, 15 breast cancers, 5 brain tumours, 3 urethral cancers. There were no HER-2 cases and and no sentinel node biopsies were performed in this series. The delay of sending specimens and receiving results via internet was one month. Sending specimens and receiving results via the Internet was one month. Apart from classifying and clarifying their diagnosis, none of these patients received specifc treatment after their immunohistochemistry result. Conclusion: Even performed free of charge, immunohistochemistry does not permit specifc treatment for Cameroonian cancer patients because they can't pay for drugs such as monoclonal antibodies. We hope the situation may change in the future.
Discovery of the Macrocycle (9E)-15-(2-(Pyrrolidin-1-yl) ethoxy)-7, 12, 25-trioxa-19, 21, 24-triaza-tetracyclo [18.3. 1.1 (2, 5). 1 (14, 18)] hexacosa-1 (24), 2, 4, 9, 14 (26), … Journal of Medicinal …, 2012
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectiv... more Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multi-parameter optimization of a key aryl ring of the previously described pacritinib (SB1518), ...
Journal of Clinical Oncology, 2012
Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway... more Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. Patients and Methods Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. Results Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area...
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Papers by kantharaj ethirajulu