title: Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δas a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.
abstract: Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinaseδ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alfaro
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Felipe
authors.initials: F
authors.lastname: Pérez de Arce
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Sebastián
authors.initials: S
authors.lastname: Belmar
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Glenda
authors.initials: G
authors.lastname: Fuentealba
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Patricio
authors.initials: P
authors.lastname: Avila
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Ureta
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Camila
authors.initials: C
authors.lastname: Flores
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Acuña
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Luz
authors.initials: L
authors.lastname: Delgado
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Diana
authors.initials: D
authors.lastname: Gaete
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Brahmam
authors.initials: B
authors.lastname: Pujala
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Anup
authors.initials: A
authors.lastname: Barde
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Nayak
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: T V R
authors.initials: TVR
authors.lastname: Upendra
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Patel
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Shailender
authors.initials: S
authors.lastname: Chauhan
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Stacy
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Ramona G
authors.initials: RG
authors.lastname: Almirez
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: David T
authors.initials: DT
authors.lastname: Hung
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Sebastián
authors.initials: S
authors.lastname: Bernales
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.).
authors.forename: Son M
authors.initials: SM
authors.lastname: Pham
authors.affiliation: Translational Research Group, Fundación Ciencia y Vida, Santiago, Chile (J.A., F.P.d.A., S.Bel., G.F., P.A., G.U., C.F., C.A., L.D., D.G.); Biological Sciences Department, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Región de Valparaíso, Chile (F.P.d.A., S.Bel.); Chemistry Group, Integral BioSciences, Pvt. Ltd., Noida, India (B.P., A.B., A.K.N., T.V.R.U., D.P., S.C., V.K.S.); and Discovery Research, Medivation, Inc., now Pfizer, San Francisco, California (S.K., R.G.A., D.T.H., S.C., R.R., S.Ber., K.P.Q., S.M.P., E.M.) Emmamccullagh@yahoo.com.
authors.forename: Emma
authors.initials: E
authors.lastname: McCullagh
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D000225:Adenine; C552946:idelalisib