Albert Lai
Novartis
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Featured researches published by Albert Lai.
Science | 2016
Konstantinos Mavrakis; E. Robert McDonald; Michael R. Schlabach; Eric Billy; Gregory R. Hoffman; Antoine deWeck; David A. Ruddy; Kavitha Venkatesan; Jianjun Yu; Gregg McAllister; Mark Stump; Rosalie deBeaumont; Samuel Ho; Yingzi Yue; Yue Liu; Yan Yan-Neale; Guizhi Yang; Fallon Lin; Hong Yin; Hui Gao; D. Randal Kipp; Songping Zhao; Joshua T. McNamara; Elizabeth R. Sprague; Bing Zheng; Ying Lin; Young Shin Cho; Justin Gu; Kenneth Crawford; David N. Ciccone
Tumors put in a vulnerable position Cancer cells often display alterations in metabolism that help fuel their growth. Such metabolic “rewiring” may also work against the cancer cells, however, by creating new vulnerabilities that can be exploited therapeutically. A variety of human tumors show changes in methionine metabolism caused by loss of the gene coding for 5-methylthioadenosine phosphorylase (MTAP). Mavrakis et al. and Kryukov et al. found that the loss of MTAP renders cancer cell lines sensitive to growth inhibition by compounds that suppress the activity of a specific arginine methyltransferase called PRMT5. Conceivably, drugs that inhibit PRMT5 activity could be developed into a tailored therapy for MTAP-deficient tumors. Science, this issue pp. 1208 and 1214 Tumors cope with a genomic change by rewiring their metabolism, but this makes them more susceptible to certain drugs. 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA–mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP–deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.
PLOS ONE | 2012
Irmgard Hofmann; Andreas Weiss; Gaelle Elain; Maria Schwaederle; Dario Sterker; Vincent Romanet; Tobias Schmelzle; Albert Lai; Saskia M. Brachmann; Mohamed Bentires-Alj; Thomas M. Roberts; William R. Sellers; Francesco Hofmann; Sauveur-Michel Maira
Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been focused on developing drugs targeting components of these pathways. To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance, we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors. Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested, demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors. We further examined signaling downstream of K-RAS, and detected a robust reduction of pERK levels upon K-RAS knock down. In contrast, no effect on pAKT levels could be observed due to almost undetectable basal expression levels. To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance, three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition. Tumors of all three models regressed upon MEK inhibition, but showed less pronounced response to PI3K inhibition. The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor. These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS.
Nature | 2017
Loren M. Lasko; Clarissa G. Jakob; Rohinton Edalji; Wei Qiu; Debra Montgomery; Enrico L. Digiammarino; T. Matt Hansen; Roberto M. Risi; Robin R. Frey; Vlasios Manaves; Bailin Shaw; Mikkel A. Algire; Paul Hessler; Lloyd T. Lam; Tamar Uziel; Emily J. Faivre; Debra Ferguson; Fritz G. Buchanan; Ruth L. Martin; Maricel Torrent; Gary G. Chiang; Kannan R. Karukurichi; J. William Langston; Brian T. Weinert; Chunaram Choudhary; Peter de Vries; John H. Van Drie; David McElligott; Ed Kesicki; Ronen Marmorstein
The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.
ACS Medicinal Chemistry Letters | 2015
Alexei Karpov; Payman Amiri; Cornelia Bellamacina; Marie-Helene Bellance; Werner Breitenstein; Dylan Daniel; Regis Denay; Doriano Fabbro; César Fernández; Inga Galuba; Stephanie Guerro-Lagasse; Sascha Gutmann; Linda Hinh; Wolfgang Jahnke; Julia Klopp; Albert Lai; Mika Lindvall; Sylvia Ma; Henrik Möbitz; Sabina Pecchi; Gabriele Rummel; Kevin Shoemaker; Joerg Trappe; Charles Voliva; Sandra W. Cowan-Jacob; Andreas Marzinzik
The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.
ACS Medicinal Chemistry Letters | 2018
Michael R. Michaelides; Arthur F. Kluge; Michael A. Patane; John H. Van Drie; Ce Wang; T. Matthew Hansen; Roberto M. Risi; Robert Mantei; Carmen Hertel; Kannan R. Karukurichi; Alexandre Nesterov; David McElligott; Peter de Vries; J. William Langston; Philip A. Cole; Ronen Marmorstein; Hong Liu; Loren M. Lasko; Kenneth D. Bromberg; Albert Lai; Edward A. Kesicki
p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.
Nature | 2018
Loren M. Lasko; Clarissa G. Jakob; Rohinton Edalji; Wei Qiu; Debra Montgomery; Enrico L. Digiammarino; T. Matt Hansen; Roberto M. Risi; Robin R. Frey; Vlasios Manaves; Bailin Shaw; Mikkel A. Algire; Paul Hessler; Lloyd T. Lam; Tamar Uziel; Emily J. Faivre; Debra Ferguson; Fritz G. Buchanan; Ruth L. Martin; Maricel Torrent; Gary G. Chiang; Kannan R. Karukurichi; J. William Langston; Brian T. Weinert; Chunaram Choudhary; Peter de Vries; Arthur F. Kluge; Michael A. Patane; John H. Van Drie; Ce Wang
In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list. Their affiliations are: I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA (A.F.K.); Mitobridge, Inc. 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.A.P.); and China Novartis Institutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China (C.W.). These authors contributed to the interpretation of results and design of compounds. In addition, author ‘Edward A. Kesicki’ was misspelled as ‘Ed Kesicki’. These errors have been corrected online.
Archive | 2006
Albert Lai; Abdallah Fanidi; Robert Booher; Christin Tse; Xie Xu; Guoying Yu; Edward Moler; Michael Rowe
Cell Reports | 2015
Julien Fitamant; Filippos Kottakis; Samira Benhamouche; Helen S. Tian; Nicolas Chuvin; Christine A. Parachoniak; Julia M. Nagle; Rushika M. Perera; Marjorie Lapouge; Vikram Deshpande; Andrew X. Zhu; Albert Lai; Bosun Min; Yujin Hoshida; Joseph Avruch; Daniela Sia; Genís Campreciós; Andrea I. McClatchey; Josep M. Llovet; David V. Morrissey; Lakshmi Raj; Nabeel Bardeesy
Cell | 2017
E. Robert McDonald; Antoine de Weck; Michael R. Schlabach; Eric Billy; Konstantinos Mavrakis; Gregory R. Hoffman; Dhiren Belur; Deborah Castelletti; Elizabeth Frias; Kalyani Gampa; Javad Golji; Iris Kao; Li Li; Philippe Megel; Thomas A. Perkins; Nadire Ramadan; David A. Ruddy; Serena J. Silver; Sosathya Sovath; Mark Stump; Odile Weber; Roland Widmer; Jianjun Yu; Kristine Yu; Yingzi Yue; Dorothee Abramowski; Elizabeth Ackley; Rosemary Barrett; Joel E. Berger; Julie L. Bernard
Archive | 2006
Albert Lai; Abdallah Fanidi; Robert Booher; Christin Tse; Xie Xu; Guoying Yu; Edward Moler; Michael Rowe