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Featured researches published by Nanxin Li.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.

Anna V. Galkin; Jonathan S. Melnick; Sungjoon Kim; Tami Hood; Nanxin Li; Lintong Li; Gang Xia; Ruo Steensma; Greg Chopiuk; Jiqing Jiang; Yongqin Wan; Peter Ding; Yi Liu; Fangxian Sun; Peter G. Schultz; Nathanael S. Gray; Markus Warmuth

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.


Journal of Medicinal Chemistry | 2013

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.

Thomas H. Marsilje; Wei Pei; Bei Chen; Wenshuo Lu; Tetsuo Uno; Yunho Jin; Tao Jiang; Sung Joon Kim; Nanxin Li; Markus Warmuth; Yelena Sarkisova; Frank Sun; Auzon Steffy; AnneMarie C. Pferdekamper; Allen Li; Sean B. Joseph; Young Chul Kim; Bo Liu; Tove Tuntland; Xiaoming Cui; Nathanael S. Gray; Ruo Steensma; Yongqin Wan; Jiqing Jiang; Greg Chopiuk; Jie Li; W. Perry Gordon; Wendy Richmond; Kevin Johnson; Jonathan Chang

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.


Biochemical Journal | 2010

Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain.

Christian C. Lee; Yong Jia; Nanxin Li; Xiuying Sun; Kenneth Ng; Eileen Ambing; Mu-Yun Gao; Su Hua; Connie Chen; Sungjoon Kim; Pierre-Yves Michellys; Scott A. Lesley; Jennifer L. Harris; Glen Spraggon

ALK (anaplastic lymphoma kinase) is an RTK (receptor tyrosine kinase) of the IRK (insulin receptor kinase) superfamily, which share an YXXXYY autophosphorylation motif within their A-loops (activation loops). A common activation and regulatory mechanism is believed to exist for members of this superfamily typified by IRK and IGF1RK (insulin-like growth factor receptor kinase-1). Chromosomal translocations involving ALK were first identified in anaplastic large-cell lymphoma, a subtype of non-Hodgkins lymphoma, where aberrant fusion of the ALK kinase domain with the NPM (nucleophosmin) dimerization domain results in autophosphosphorylation and ligand-independent activation. Activating mutations within the full-length ALK kinase domain, most commonly R1275Q and F1174L, which play a major role in neuroblastoma, were recently identified. To provide a structural framework for understanding these mutations and to guide structure-assisted drug discovery efforts, the X-ray crystal structure of the unphosphorylated ALK catalytic domain was determined in the apo, ADP- and staurosporine-bound forms. The structures reveal a partially inactive protein kinase conformation distinct from, and lacking, many of the negative regulatory features observed in inactive IGF1RK/IRK structures in their unphosphorylated forms. The A-loop adopts an inhibitory pose where a short proximal A-loop helix (alphaAL) packs against the alphaC helix and a novel N-terminal beta-turn motif, whereas the distal portion obstructs part of the predicted peptide-binding region. The structure helps explain the reported unique peptide substrate specificity and the importance of phosphorylation of the first A-loop Tyr1278 for kinase activity and NPM-ALK transforming potential. A single amino acid difference in the ALK substrate peptide binding P-1 site (where the P-site is the phosphoacceptor site) was identified that, in conjunction with A-loop sequence variation including the RAS (Arg-Ala-Ser)-motif, rationalizes the difference in the A-loop tyrosine autophosphorylation preference between ALK and IGF1RK/IRK. Enzymatic analysis of recombinant R1275Q and F1174L ALK mutant catalytic domains confirms the enhanced activity and transforming potential of these mutants. The transforming ability of the full-length ALK mutants in soft agar colony growth assays corroborates these findings. The availability of a three-dimensional structure for ALK will facilitate future structure-function and rational drug design efforts targeting this receptor tyrosine kinase.


ACS Medicinal Chemistry Letters | 2012

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Pam Albaugh; Yi Fan; Yuan Mi; Fangxian Sun; Francisco Adrian; Nanxin Li; Yong Jia; Yelena Sarkisova; Andreas Kreusch; Tami Hood; Min Lu; Guoxun Liu; Shenlin Huang; Zuosheng Liu; Jon Loren; Tove Tuntland; Donald S. Karanewsky; H. Martin Seidel; Valentina Molteni

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.


Clinical Cancer Research | 2017

Dual ALK and CDK4/6 inhibition demonstrates on-target synergy against neuroblastoma

Andrew C. Wood; Kateryna Krytska; Hannah Ryles; Nicole R. Infarinato; Renata Sano; Theodore D. Hansel; Lori S. Hart; Frederick J. King; Timothy R. Smith; Edward Ainscow; Kathryn B. Grandinetti; Tove Tuntland; Sunkyu Kim; Giordano Caponigro; You Qun He; Shiva Krupa; Nanxin Li; Jennifer L. Harris; Yael P. Mosse

Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine whether drug combinations could enhance antitumor efficacy. Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug–drug interactions. Results: The combination of ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity (P = 0.008) and synergy scores (P = 0.006) in cell lines with ALK mutations as compared with cell lines lacking mutations or alterations in ALK. Compared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with ALK-F1174L and F1245C de novo resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy. Conclusions: This preclinical combination drug screen with in vivo validation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population. Clin Cancer Res; 23(11); 2856–68. ©2016 AACR.


ACS Medicinal Chemistry Letters | 2015

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

Ha-Soon Choi; Paul Vincent Rucker; Zhicheng Wang; Yi Fan; Pamela A. Albaugh; Greg Chopiuk; Francois Gessier; Fangxian Sun; Francisco Adrian; Guoxun Liu; Tami Hood; Nanxin Li; Yong Jia; Jianwei Che; Susan McCormack; Allen Li; Jie Li; Auzon Steffy; AnneMarie Culazzo; Celine Tompkins; Van Phung; Andreas Kreusch; Min Lu; Bin Hu; Apurva Chaudhary; Mahavir Prashad; Tove Tuntland; Bo Liu; Jennifer L. Harris; H. Martin Seidel

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.


Molecular Cancer Therapeutics | 2011

Abstract B232: Activity of a potent and selective phase I ALK inhibitor LDK378 in naive and crizotinib-resistant preclinical tumor models.

Nanxin Li; Pierre-Yves Michellys; Sungjoon Kim; AnneMarie Culazzo Pferdekamper; Jie Li; Shailaja Kasibhatla; Celin Tompkins; Auzon Steffy; Allen Li; Frank Sun; Xiuying Sun; Su Hua; Ralph Tiedt; Yelena Sarkisova; Thomas H. Marsilje; Peter McNamara; Jennifer L. Harris

A c-MET/ALK kinase inhibitor crizotinib has demonstrated significant activity in lung cancer patients with EML4-ALK in clinical studies. However relapse (or acquired resistance) has also been reported. We have developed crizotinib resistant tumor models and used the models to evaluate the ALK inhibitor LDK378. LDK378 is a potent and selective ALK inhibitor that does not cross react with c-MET. In a mouse xenograft tumor model derived from the EML4-ALK+ lung cancer cell line NCI-H2228, LDK378 caused complete tumor regression when dosed orally at 25 mg/kg/day. After tumor bearing animals had been treated with LDK378 at 50 mg/kg/day for 14 days, remission was maintained for more than 4 months. In several NCI-H2228 tumor models that were induced to become resistant to crizotinib, LDK378 demonstrated efficacy at 50 mg/kg/day. Based on 4-wk GLP toxicology studies the drug exposure associated with this dose is predicted to be below the exposure at the MTD in humans. ALK resistance mutations reported in crizotinib relapsed patients were also found in the crizotinib resistant NCI-H2228 tumor models. The results from these preclinical studies suggest that LDK378 may be active in crizotinib-relapsed patients. A phase I clinical study of LDK378 has recently begun in both crizotinib-relapsed and crizotinib-naive patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B232.


Bioorganic & Medicinal Chemistry Letters | 2016

Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.

Pierre-Yves Michellys; Bei Chen; Tao Jiang; Yunho Jin; Wenshuo Lu; Thomas H. Marsilje; Wei Pei; Tetsuo Uno; Xuefeng Zhu; Baogen Wu; Truc Ngoc Nguyen; Badry Bursulaya; Christian C. Lee; Nanxin Li; Sungjoon Kim; Tove Tuntland; Bo Liu; Frank Sun; Auzon Steffy; Tami Hood

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.


Cancer Research | 2010

Abstract 20: Raf kinase inhibitors can induce Raf dimerization, downstream signaling, and cell growth

Tobi Nagel; Kevin Shoemaker; Nanxin Li; Marco Wallroth; Hanne Merritt; John Chan; Susan Kaufman; Brent A. Appleton; Yongjin Xu; Matthew Holderfield; Daniel Poon; John Tellew; Darrin Stuart

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Genetic alterations in the Ras/Raf/MEK/ERK pathway are among the most common in human cancers. Up to 70% of melanomas harbor B-Raf mutations, and roughly 90% of pancreatic tumors have K-Ras mutations. To address these Raf pathway-driven cancers, small molecule Raf kinase inhibitors have been developed and are currently under clinical investigation. In B-RafV600E cells, Raf compounds inhibit signaling through MEK and ERK, resulting in the expected anti-proliferative effects. Paradoxically, in wild-type Raf cells and in mutant Ras cells, these compounds induce downstream signaling and can induce cell growth in some settings in vitro. While the induction of downstream signaling has previously been attributed to published Raf pathway feedback loops, this has not been proven directly. In fact, we show here that induction of pMEK and pERK can occur within minutes of Raf compound treatment, even before reported feedback phosphorylation events are seen on B-Raf and C-Raf. Interestingly, the induction of signaling and cell growth both occur in a biphasic pattern, with low compound concentrations (0.01-0.1 uM) causing maximal induction, and higher compound concentrations (1-10 uM) causing less profound induction. Such a biphasic pattern is also observed in biochemical assays with purified wild-type B-Raf or C-Raf. The biphasic pattern is suggestive of a mechanism involving the interaction of two signaling subunits. In addition, recent literature data (Rajakulendran, Nature, 461:542-6) has demonstrated that Raf dimerization can upregulate pMEK, not through trans-phosphorylation of Raf molecules but presumably by conformational activation of the kinase. Consistent with that model, we show that Raf compound treatment induces B/C-Raf dimer formation in cells. In addition, knockdown of A-, B- or C-Raf with siRNA does not abrogate the Raf compound induction of pMEK and pERK, suggesting that induction might be mediated by Raf homo- as well as hetero-dimerization. Notably, knockdown of K-Ras in K-RasMUT cells also does not abolish the induction, implying that this effect is not mediated by Ras. Taken together, these data suggest a model in which compound binding to one Raf molecule induces dimerization and conformational activation of a partner Raf molecule in the dimer. These observations can explain why wild-type Raf and mutant Ras tumors are insensitive to selective Raf kinase inhibitors and might also have important implications for toxicity, since induction of strong mitogenic signaling could lead to hyperproliferation of normal tissues. Understanding the Raf compound induction mechanism may lead not only to the design of improved inhibitors, but also to methods for overcoming the induction seen with current development compounds. Toward that end, we show that combining a MEK inhibitor with a Raf compound causes inhibition of both pERK and cell growth and may therefore have significant advantages in the clinic. 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 20.


Cancer Research | 2010

Abstract 2620: The Cancer Cell Line Encyclopedia project: From integrative cancer genomics to personalized cancer therapy

Jordi Barretina; Giordano Caponigro; Sungjoon Kim; Nicolas Stransky; Kavitha Venkhatesan; Venkateshwar A. Reddy; Michael F. Berger; Michael Morrissey; Paula Morais; Jodi Meltzer; Joseph Thibault; Scott Mahan; Dmitriy Sonkin; John Che; Pichai Raman; Jessica Slind; Cory M. Johannessen; Supriya Gupta; Lili Niu; Sarah M. Kehoe; Charlie Hatton; Michael D. Jones; John E. Monahan; Vic Meyer; Christopher J. Wilson; Aaron Shipway; Nanxin Li; Ingo H. Engels; Andrew I. Su; Adam Callahan

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Cancer genome characterization efforts such as The Cancer Genome Atlas project are rapidly improving our knowledge of tumor genetic alterations. With the expanded use of massively parallel sequencing, the catalogue of known genetic alterations in cancer is expected to expand at an accelerating rate. In this context, the emphasis is shifting towards systematic identification of the genes and pathways targeted by recurrent genetic alterations, their functional impact in tumor biology, and the resulting cellular dependencies that might be exploited therapeutically. Anticipating the need for a companion resource to systematically probe tumor biology armed with cancer genomics knowledge, we have assembled a compendium of experimentally tractable cancer model systems consisting of ∼1000 human cancer cell lines and performed extensive genomic analysis (at the level of gene expression, DNA copy number and mutations) coupled with pharmacological profiling. This resource, which we call the Cancer Cell Line Encyclopedia (CCLE), is being used not only to identify the putative targets of prevalent genetic alterations, but also to systematically link the presence or absence of certain genetic alterations to drug sensitivity or resistance. To date, we have identified several previously unappreciated genomic predictors of response or intrinsic resistance to targeted anticancer agents. For instance, through integrative analysis, we have discovered additional mechanisms that may underlie sensitivity to MET inhibitors, beyond amplification of the MET receptor, highlighting the fact that response prediction in the clinic may require assessment of multiple variables. We have also broadened the potential relevance of known predictive biomarkers that might provide a rationale for future genotype-driven clinical trials. As an example, we have expanded on existing knowledge of resistance to receptor tyrosine kinase (RTK) inhibitors, showing that the presence of RAS mutations may predict lack of response to a broad spectrum of RTK inhibitors in addition to EGFR inhibitors. This work demonstrates that pharmacological profiling of large, genomically-annotated cancer model systems may uncover new tumor dependencies as well as positive and negative predictors of drug response. The results of this study are being made publicly available at a CCLE online portal, with the hope they will become a valuable resource for the cancer community to propel translation of the knowledge generated through in vitro integrative genomics into personalized cancer medicine. 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 2620.

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Dive into the Nanxin Li's collaboration.

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Jennifer L. Harris

Genomics Institute of the Novartis Research Foundation

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Sungjoon Kim

Genomics Institute of the Novartis Research Foundation

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Tove Tuntland

Genomics Institute of the Novartis Research Foundation

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Auzon Steffy

Genomics Institute of the Novartis Research Foundation

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Bo Liu

Genomics Institute of the Novartis Research Foundation

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Jie Li

Genomics Institute of the Novartis Research Foundation

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Pierre-Yves Michellys

Genomics Institute of the Novartis Research Foundation

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Thomas H. Marsilje

Genomics Institute of the Novartis Research Foundation

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