Table S3 from IOA-244 is a non-ATP-competitive, highly selective, tolerable phosphoinositide 3-kinase delta inhibitor that targets solid tumors and breaks immune tolerance
Zoë JohnsonChiara TarantelliElisa CivanelliLuciano CascioneFilippo SprianoAmy FraserPritom ShahTyzoon NomanbhoySara NapoliAndrea RinaldiKarolina Niewola-StaszkowskaMichael LahnDominique PerrinMathias WenesDenis MiglioriniFrancesco BertoniLars van der VeenGiusy Di Conza
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Abstract The PIM family of serine/threonine kinases are pro-proliferative kinases activated by multiple cytokines and growth factor signaling. The Pim kinases are unusual in that they are regulated primarily by transcription and not by membrane recruitment or phosphorylation like other serine/threonine kinases. Activated cytokine receptors recruit JAKs to induce STAT-dependent transcription of the Pim genes. They are proto-oncogenes and have been implicated in the process of lymphomagenesis and malignant transformation. Pim overexpression has been reported in diffuse B cell lymphoma, chronic lymphocytic leukemia, FLT3-mediated acute myelogenous leukemia and prostate cancer. Pim-2 is over expressed in leukemias and lymphomas, whereas Pim-3 overexpression has been observed in melanoma, pancreatic and gastric tumors. The recent reports of elevated levels of Pim-1 expression in human prostate tumor biopsies implicate the Pim family of protein kinases in the progression of human prostate tumors. Further, in transgenic animal models, Pim-1 expression has been shown to be elevated in prostate tumors that are caused by overexpression of the c-myc oncogene. Recent evidence reveals the overlapping and compensatory nature of Pim-1 and Pim-2 phosphorylation and highlights the importance of inhibiting all isoforms. The emerging role of the PIM kinase family in hematological malignancies and solid tumors and the druggable nature of their ATP binding pocket make them attractive targets for anticancer drug development. Utilizing a highly distinct molecular scaffold, CX-6258 was developed as a selective and potent small molecule pan-PIM kinase inhibitor. CX-6258 inhibits Pims 1, 2 and 3 with IC50 values in the low nanomolar range and high selectivity as evidenced in a screening panel of over 100 kinases. CX-6258 demonstrates potent in vitro antiproliferative activity, particularly in leukemia derived cell lines expressing the FLT3-ITD. Moreover, CX-6258 inhibits the phosphorylation of BAD and 4EBP1, known substrates for PIMs 1, 2 and 3. When delivered orally, this pan-Pim inhibitor is well tolerated and demonstrates potent antitumor activity in murine xenograft models of PIM driven cancer. Using CX-6258 as our “path finder” molecule, we have created four additional unique chemical scaffolds as pan-Pim inhibitors, and certain molecules from these scaffolds can inhibit Pims 1, 2 and 3 in the picomolar range while exhibiting no inhibitory activity of the Flt3 protein kinase. The in vivo and in vitro profiles of these chemically diverse series are indicative of an effective and potent anti-cancer mechanism mediated through the selective inhibition of PIM kinase activity. Together, these findings exemplify that we have created multiple proprietary chemical series of pan-Pim inhibitors exhibiting picomolar potency and discerning selectivity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A246.
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Dabrafenib was recently approved by the US Food and Drug Administration for treatment of unresectable or metastatic melanoma with BRAF V600E mutations as detected by an FDA-approved test. The THxID BRAF assay, for detection of BRAF V600E mutations was concurrently approved. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, because of the potential risk of tumor promotion. About 50% of melanomas have an activating mutation in the BRAF gene, with about 80%-90% of those having a V600E mutation, and 10%-20% having a V600K mutation. Dabrafenib is a reversible, ATP-competitive inhibitor that selectively inhibits BRAF V600E kinase; preclinical data indicate that dabrafenib inhibits the MAPK pathway in BRAF V600E-mutated melanoma cells, leading to decreased proliferation and regression in xenograft models. Dabrafenib also inhibits other mutated forms of BRAF kinases, including BRAF V600K and BRAF V600D enzymes and, at higher concentrations, wild-type BRAF and CRAF kinases and other kinases (eg, SIK1, NEK11, and LIMK1). However, in vitro experiments have shown paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors.
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Abstract The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF, NRAS and KRAS is considered one of the causes of solid tumors (NSCLC, CRC,HCC, andthyroid cancers) and hematologic malignancies. HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM). HM95573 potently inhibited the growth of BRAFmutation CRC cell lines (e.g. IC50: 118nM for Colo-205) and thyroid cancer cell lines (43nM for B-CPAP); KRAS mutation NSCLC cell lines(297nM for Calu-6),CRC cell lines(65nM for HCT-116) and thyroid cancer cell lines(479nM for CAL-62); and NRAS mutation HCC cell lines(28nM for HepG2) andleukemia cell lines (39nM for HL-60). HM95573 effectively inhibited the phosphorylations of MEK and ERK, downstream kinases associated with cell proliferation in tumor cell lines mutated in BRAF, KRAS and NRAS. In addition, the phosphorylation of downstream kinases of RAF such as MEK and ERK was effectively inhibited with treatment of HM95573 in mutant KRAS NSCLC and CRC cells. HM95573 showed the excellent antitumor activity in mouse models xenografted with BRAF mutation cell line (Colo-205), KRAS mutation cell lines (Calu-6 and HCT-116)and NRAS mutation cell line (HepG2)two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. The in vivo antitumor activity of HM95573 was potentiated with MEK inhibitors. Now, HM95573 is currently in phase I development in patients with advanced solid tumors including KRAS mutation NSCLC in Korea. Citation Format: Young-Mi Lee, InHwan Bae, Namgoong Gwang Mo, Jae Ho Lee, Suhyeon Kim, Ji Yeon Song, Kyu Hang Lee, Tae Hun Song, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in solid tumors and hematologic malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2607. doi:10.1158/1538-7445.AM2015-2607
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Abstract Introduction JI-101 is a highly selective and potent angiogenesis inhibitor with unique EphB4 activity that distinguishes it from other agents in clinical development. We report the preclinical pharmacology and early clinical experience with this compound. Procedures Lead optimization was used to identify cgi1842 (now JI-101) with a targeted activity profile that is selective and unique. JI-101 was tested in binding, enzymatic, and cell-based assays for activity against kinase and non-kinase targets. Preclinical in vivo testing for PK, PD, efficacy, and safety pharmacology was performed in mouse, rat, guinea pig, and dog. A Phase I clinical trial is underway: 12 patients have been treated thus far with 28-day oral daily dosing at 100 mg, 200 mg, 400 mg QD or at 200 mg BID. PK, PD, and imaging analyses have been performed. Data JI-101 has a MW of 466D and high (<100 nm) potency against VEGFR2, EphB4, and PDGFR in enzymatic and cell-based assays. Broad kinase cross-screening (Ambit KinomeScan, 445 kinases) reveals that JI-101 is highly selective for angiogenic kinases with only 23 kinases demonstrating a Kd 15). JI-101 was co-administered with paclitaxel in a MDA-MB-231 mouse xenotransplant model, resulting in greater efficacy and no increased toxicity. Based on 28-day GLP toxicology studies conducted in rat and dog, a 100 mg qd starting dose (2 × 50 mg capsules) was chosen for Phase I studies. JI-101 appears to be very well-tolerated to date with no dose limiting toxicities. Patients have received 1-9 cycles with most receiving multiple cycles and 5 remain on study at 100 mg (1 pt), 200 mg (1 pt), and 400 mg (3 pt). Manageable hypertension has been seen in all cohorts indicating a possible PD effect. Hand-foot syndrome of short duration was seen at the 400mg dose level. Further clinical details of the PK, PD, tolerability and efficacy of JI-101 will be presented. Conclusions JI-101 potently inhibits 3 critical angiogenic kinases (VEGFR2, EphB4, and PDGFR) and is the only such “triple” angiogenesis inhibitor currently in development. JI-101 shows robust preclinical and clinical pharmacology and is well-tolerated to date in human trials. In tumors where EphB4 may play an oncogenic role, such as head and neck cancer, JI-101 may have anti-proliferative effects in addition to anti-angiogenic effects and should be amenable to combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 17.
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Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies.
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PIM (proviral integration site for moloney murine leukemia virus) kinase plays a key role as an oncogene in various cancers including myeloma, leukemia, prostate and breast cancers.The aberrant expression and/or activation of PIM kinases in various cancers follow an isoform-specific pattern.While PIM1 is predominantly expressed in hematological and solid tumors, PIM2 and PIM3 are largely expressed in leukemia and solid tumors, respectively.All of PIM kinases cause transcriptional activation of genes involved in cell survival and cell cycle progression in cancer.A variety of pro-tumorigenic signaling molecules, such as MYC, p21Cip1/Waf1 /p27 kip1 , CDC25, Notch1 and BAD have been identified as the downstream targets of PIM kinases.So far, three kinds of adenosine triphosphate-competitive PIM inhibitors, SGI-1776, AZD1208, and LGH447 have been in clinical trials for the treatment of acute myelogenous leukemia, prostate cancer, lymphoma, or multiple myeloma.This review sheds light on the signaling pathways involved in the PIM kinase regulation and current status of developing PIM kinase inhibitors as clinical success in combating human cancer.
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5261 Since the successful use of kinase inhibitors in the clinical setting (e.g., Gleevec and Iressa), kinases have become an area of intense focus in the search for oncogene candidates. Based on our array CGH (Comparative Genomic Hybridization) and SAGE (Serial Analysis of Gene Expression) data on breast tumors, we selected 22 kinases that were both amplified and overexpressed in breast tumors as candidate oncogenic kinases. Quantitative PCR (QPCR) was performed to verify amplification and overexpression of these kinases in 30 breast tumors using genomic DNA and cDNAs, respectively. The result was further confirmed using additional samples from 13 breast tumors which had not been analyzed by array CGH. This lead us to find 9 kinases that were amplified to different degrees in breast tumors and had concomitant overexpression when compared to normal breast tissues. Among these putative oncogenes we focused on IKBKE, which encode IkB kinase epsilon (IKKe), a kinase involved in NF-kB and interferon activation. Array CGH analysis and QPCR demonstrated that IKBKE was gained or amplified in at 10 of 30 breast tumors, which is accompanied by overexpression in at least 8 tumors. It is also amplified/gained and overexpressed in three breast cancer cell lines (ZR75-1, UACC812, and MCF-7). QPCR also detected overexpression of IKKe in non-amplified tumors and cell lines, suggesting other mechanisms are involved in IKKe upregulation. We demonstrated that overexpression of IKKe lead to transformation of kidney embryonic cells, while downregulation of IKKe by RNAi inhibited growth of ZR75-1 and MCF-7 breast cancer cells. Thus, IKBKE represents a promising oncogene candidate that function through activation of NF-kB in breast cancers and a promising therapeutic target.
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