Drug discovery in the next decade: innovation needed ASAP.

Pharmaceutical companies must find a better way to increase their output of truly new drugs for the benefit of patients and for their business survival. Here, I highlight a general perspective from within pharmaceutical research as it pertains to research advances in chemistry, biology, pharmacology, pharmacokinetics and toxicology that, if well integrated, stands to put the industry on a productive path. In addition, I provide a complementary perspective on the corporate culture aspect of innovation. I also introduce a new concept, termed 'innovation ASAP' (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provide support for it using examples of several successful drugs.

[1]  R. Dror,et al.  Long-timescale molecular dynamics simulations of protein structure and function. , 2009, Current opinion in structural biology.

[2]  B. Munos Lessons from 60 years of pharmaceutical innovation , 2009, Nature Reviews Drug Discovery.

[3]  Paul A Clemons,et al.  Connecting synthetic chemistry decisions to cell and genome biology using small-molecule phenotypic profiling. , 2009, Current opinion in chemical biology.

[4]  Huang,et al.  Synthesizing Our Future , 2011 .

[5]  R. Aldrich,et al.  Allosteric Voltage Gating of Potassium Channels I: Mslo Ionic Currents in the Absence of Ca2+ , 1999 .

[6]  Stephen P. Hale,et al.  The exploration of macrocycles for drug discovery — an underexploited structural class , 2008, Nature Reviews Drug Discovery.

[7]  Tudor I. Oprea,et al.  The Design of Leadlike Combinatorial Libraries. , 1999, Angewandte Chemie.

[8]  Malcolm Rowland,et al.  Physiologically-based pharmacokinetics in drug development and regulatory science. , 2011, Annual review of pharmacology and toxicology.

[9]  F. Koehn,et al.  The evolving role of natural products in drug discovery , 2005, Nature Reviews Drug Discovery.

[10]  Glenn D Prestwich,et al.  Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery. , 2008, Accounts of chemical research.

[11]  F. Tally,et al.  Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. , 2005, The Journal of antimicrobial chemotherapy.

[12]  S. Mitsuhashi,et al.  Gastrointestinal motor-stimulating activity of macrolide antibiotics and analysis of their side effects on the canine gut , 1984, Antimicrobial Agents and Chemotherapy.

[13]  A. Terzic,et al.  Channelopathies: Decoding Disease Pathogenesis , 2010, Science Translational Medicine.

[14]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[15]  Darrell M. Wilson,et al.  Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. , 2006, The Journal of clinical endocrinology and metabolism.

[16]  K. Bui,et al.  Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate. , 2010, Bioorganic & medicinal chemistry letters.

[17]  T. J. Peters,et al.  The Circle of Innovation : You Can't Shrink Your Way to Greatness , 1999 .

[18]  Willem Soudijn,et al.  Allosteric modulation of G-protein-coupled receptors , 2001 .

[19]  Stanley Goldberg,et al.  Discovering: Inventing and Solving Problems at the Frontiers of Scientific Knowledge , 1997 .

[20]  Jóhannes Reynisson,et al.  Characteristics of known drug space. Natural products, their derivatives and synthetic drugs. , 2010, European journal of medicinal chemistry.

[21]  Jilly F. Evans,et al.  Receptor for motilin identified in the human gastrointestinal system. , 1999, Science.

[22]  Karl T. Ulrich,et al.  Innovation Tournaments: Creating and Selecting Exceptional Opportunities , 2009 .

[23]  Baoguang Zhao,et al.  Design, synthesis and selection of DNA-encoded small-molecule libraries. , 2009, Nature chemical biology.

[24]  Anna Vulpetti,et al.  Predicting Polypharmacology by Binding Site Similarity: From Kinases to the Protein Universe , 2010, J. Chem. Inf. Model..

[25]  Arthur Christopoulos,et al.  Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders , 2009, Nature Reviews Drug Discovery.

[26]  Dimitris K Agrafiotis,et al.  SAR maps: a new SAR visualization technique for medicinal chemists. , 2007, Journal of medicinal chemistry.

[27]  Renée Mauborgne,et al.  Blue ocean strategy : how to create uncontested market space and make the competition irrelevant , 2005 .

[28]  G. Festel Outsourcing chemical synthesis in the drug discovery process. , 2011, Drug discovery today.

[29]  Thomas J Walsh,et al.  Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. , 2004, The New England journal of medicine.

[30]  Emanuele Perola,et al.  An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. , 2010, Journal of medicinal chemistry.

[31]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[32]  A. Kwong,et al.  Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease , 2006, Antimicrobial Agents and Chemotherapy.

[33]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[34]  A. Chadwick,et al.  Overcoming psychological barriers to good discovery decisions. , 2010, Drug discovery today.

[35]  H. Schaffhauser,et al.  Allosteric approaches to the targeting of G-protein-coupled receptors for novel drug discovery: a critical assessment. , 2007, Biochemical pharmacology.

[36]  Hirotaka Takeuchi,et al.  Extreme Toyota: Radical Contradictions That Drive Success at the World's Best Manufacturer , 2008 .

[37]  P. Lewi,et al.  Memorial issue in honor of Dr. Paul A. J. Janssen. , 2005, Journal of medicinal chemistry.

[38]  A. Sands,et al.  Knockouts model the 100 best-selling drugs—will they model the next 100? , 2003, Nature Reviews Drug Discovery.

[39]  D. Selkoe Folding proteins in fatal ways , 2003, Nature.

[40]  D. Kern,et al.  Dynamic personalities of proteins , 2007, Nature.

[41]  Baran,et al.  The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century. , 2000, Angewandte Chemie.

[42]  J. Brown,et al.  Motilin, a gastric motor activity stimulating polypeptide: the complete amino acid sequence. , 1973, Canadian journal of biochemistry.

[43]  S. Strom,et al.  Chimeric mice with humanized liver: tools for the study of drug metabolism, excretion, and toxicity. , 2010, Methods in molecular biology.

[44]  B. Barlogie,et al.  Antitumor activity of thalidomide in refractory multiple myeloma. , 1999, The New England journal of medicine.

[45]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. , 1978, The Journal of antibiotics.

[46]  Anne Mai Wassermann,et al.  SARANEA: A Freely Available Program To Mine Structure-Activity and Structure-Selectivity Relationship Information in Compound Data Sets , 2010, J. Chem. Inf. Model..

[47]  H. Davis,et al.  The target of ezetimibe is Niemann – Pick C 1-Like 1 ( NPC 1 L 1 ) , 2005 .

[48]  D. Cavalla,et al.  Does R&D pay? , 2010, Drug discovery today.

[49]  Jiri Aubrecht,et al.  Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact , 2010, Nature Reviews Drug Discovery.

[50]  P. Sexton,et al.  Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. , 2007, Trends in pharmacological sciences.

[51]  Clive N. Svendsen,et al.  Human stem cells and drug screening: opportunities and challenges , 2010, Nature Reviews Drug Discovery.

[52]  P. Khavari,et al.  Use of human tissue to assess the oncogenic activity of melanoma-associated mutations , 2005, Nature Genetics.

[53]  Eric Bonabeau,et al.  A Drug Candidate Design Environment Using Evolutionary Computation , 2008, IEEE Transactions on Evolutionary Computation.

[54]  Bethan Hughes,et al.  2009 FDA drug approvals , 2010, Nature Reviews Drug Discovery.

[55]  J. Clader The discovery of ezetimibe: a view from outside the receptor. , 2004, Journal of medicinal chemistry.

[56]  Jie Yang,et al.  Integration TRIZ with problem-solving tools: a literature review from 1995 to 2006 , 2006 .

[57]  F. Maltais,et al.  In vitro and in vivo isotope effects with hepatitis C protease inhibitors: enhanced plasma exposure of deuterated telaprevir versus telaprevir in rats. , 2009, Journal of medicinal chemistry.

[58]  M. Edwards,et al.  Using the Golden Triangle to optimize clearance and oral absorption. , 2009, Bioorganic & medicinal chemistry letters.

[59]  Christopher T. Walsh,et al.  Drugs as materials: valuing physical form in drug discovery , 2004, Nature Reviews Drug Discovery.

[60]  Michael Williams,et al.  Productivity Shortfalls in Drug Discovery: Contributions from the Preclinical Sciences? , 2011, Journal of Pharmacology and Experimental Therapeutics.

[61]  M. Potashman,et al.  Covalent modifiers: an orthogonal approach to drug design. , 2009, Journal of medicinal chemistry.

[62]  T. Hoffmann,et al.  The future of discovery chemistry: quo vadis? Academic to industrial--the maturation of medicinal chemistry to chemical biology. , 2010, Drug discovery today.

[63]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[64]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[65]  J. Hughes,et al.  Physiochemical drug properties associated with in vivo toxicological outcomes. , 2008, Bioorganic & medicinal chemistry letters.

[66]  E. Bonabeau Don't trust your gut. , 2003, Harvard business review.

[67]  James Inglese,et al.  High Throughput Screening (HTS) Techniques: Applications in Chemical Biology , 2008 .

[68]  Marcy J. Balunas,et al.  Drug discovery from natural sources , 2006, The AAPS Journal.

[69]  J. Blaivas,et al.  Crossing the line , 2002, Neurourology and urodynamics.

[70]  T. Kenakin G-protein coupled receptors as allosteric machines. , 2004, Receptors & channels.

[71]  L. Knutsen Drug discovery management, small is still beautiful: Why a number of companies get it wrong. , 2011, Drug discovery today.

[72]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[73]  M. Hidalgo,et al.  Targeting mTOR for cancer treatment. , 2006, Current opinion in investigational drugs.

[74]  C. Lipinski Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[75]  Dmitry M Korzhnev,et al.  Probing invisible, low-populated States of protein molecules by relaxation dispersion NMR spectroscopy: an application to protein folding. , 2008, Accounts of chemical research.

[76]  T. Kenakin New Concepts in Drug Discovery: Collateral Efficacy and Permissive Antagonism , 2005, Nature Reviews Drug Discovery.

[77]  F. Gonzalez,et al.  Humanized Mouse Lines and Their Application for Prediction of Human Drug Metabolism and Toxicological Risk Assessment , 2008, Journal of Pharmacology and Experimental Therapeutics.

[78]  B. Hawes,et al.  The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Ruili Huang,et al.  The future of toxicity testing: a focus on in vitro methods using a quantitative high-throughput screening platform. , 2010, Drug discovery today.

[80]  L. Dick,et al.  Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. , 1998, Bioorganic & medicinal chemistry letters.

[81]  Christopher G Newton,et al.  Outsourcing lead optimisation--the quiet revolution. , 2004, Drug discovery today.

[82]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[83]  Richard W. Aldrich,et al.  Coupling between Voltage Sensor Activation, Ca2+ Binding and Channel Opening in Large Conductance (BK) Potassium Channels , 2002, The Journal of general physiology.

[84]  David B. Searls,et al.  Can literature analysis identify innovation drivers in drug discovery? , 2009, Nature Reviews Drug Discovery.

[85]  H. Brunner,et al.  Aliskiren: the first renin inhibitor for clinical treatment , 2008, Nature Reviews Drug Discovery.

[86]  G. Terstappen,et al.  Target deconvolution strategies in drug discovery , 2007, Nature Reviews Drug Discovery.

[87]  Burkhard Haefner,et al.  Drugs from the deep: marine natural products as drug candidates. , 2003, Drug discovery today.

[88]  Yong Zhao,et al.  Mouse models with human immunity and their application in biomedical research , 2008, Journal of cellular and molecular medicine.

[89]  T. Kenakin Allosteric Agonist Modulators , 2007, Journal of receptor and signal transduction research.

[90]  J. Changeux,et al.  ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL. , 1965, Journal of molecular biology.

[91]  K. Kehn-Hall,et al.  The utilization of humanized mouse models for the study of human retroviral infections , 2009, Retrovirology.

[92]  M. Manns,et al.  Humanized mice for modeling human infectious disease: challenges, progress, and outlook. , 2009, Cell host & microbe.