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Targeting endogenous inhibitors of apoptosis: Opportunities for the treatment of cancer, stroke and MS

  • ID: 10796
  • Report
  • January 2003
  • 65 pages
  • Lead Discovery
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It is now well established that cellular suicide (apoptosis or programmed cell death) is central to a number of physiological cellular processes and is essential in the maintenance of homeostasis and survival of multicellular organisms. Equally, or perhaps even more important is the role of apoptosis in the pathogenesis of many human diseases.

Apoptosis stimulators have emerged as key targets for the control of cancer. This therapeutic class has, however, remained predominantly experimental and of the 100 or so molecules in development as apoptosis agonists, approaching 70% of these remain in preclinical development. The low rate of clinical entry associated with these molecules is related to lack of specificity, low efficacy and/or susceptibility to drug resistance. These issues are being addressed as our understanding of the field evolves, and as a result, the identification and exploitation of new targets remains a considerable focus of attention - indeed the number of pro-apoptotic molecules in preclinical development has risen by about 10-fold since 1995

From a molecular point of view this field concentrated heavily on the caspases and endogenous inhibitors of apoptosis, predominantly Bcl-2 proteins. Over the past few years a considerable amount of research has been conducted and our view of apoptosis has changed dramatically. Major advances have included the emergence of the IAP ("Inhibitor of Apoptosis Proteins") family. This field has grown exponentially since 1995 and continues to do so. Although Xiap and survivin remain the better known members of this family, 8 human IAPs have now been identified. Members of this family represent perhaps the most important regulators of apoptosis by virtue of the fact that they intercept and regulate two convergent apoptotic pathways - the extrinsic (receptor-mediated) and intrinsic (mitochondria-mediated) pathway. Each of the IAPs has a distinct profile, with respect to their influence over apoptosis pathways, their mechanism of action and their regulation. Furthermore our increased understanding of apoptosis has lead to the emergence of members of the IAP family as therapeutic targets for the treatment of stroke and multiple sclerosis as well as cancer. In short the IAPs, if harnessed, will offer targeted and highly effective control over apoptosis and over diverse diseases.

Considering the therapeutic importance of the IAP family, LeadDiscovery in collaboration with Martin Holcik from the University of Ottawa has produced a state of the art report of this field.

The dossier opens with a general introduction to the apoptosis pathway which continues into a detailed characterization of the various member of the IAP family including an account of their involvement in apoptosis, their mechanism of action and their regulation. The involvement of apoptosis in cancer, stroke and angiogenesis (which plays a role in both of these conditions) as well as multiple sclerosis is then discussed with particular attention being given to the role of the IAP family in these diseases. Furthermore, available data describing the therapeutic effects of modulating family members and strategic insights into how modulation of IAP activity can be achieved is provided.

The dossier then continues with an analysis of development activity in the field, profiling apoptosis agonists and antagonists in development. The report concludes with an assessment of patent activity surrounding the IAP family. In short this report provides an in depth view of this emerging therapeutic field offering a comprehensive analysis of the cellular biology, therapeutic activity and pharmaceutical potential of this recently emerging target.

Following an expansion of LeadDiscovery's PharmaceuticalSolutions service we are now able to provide expert advice on medicinal chemistry surrounding the development of IAP modulators, chemical libraries of candidate modulators and screening services to assay such libraries. Consequently, this dossier like all of our dossiers not only offers a strategic insight into this field and an opportunity to expedite target selection but they can also be used as a platform from which to rapidly develop therapeutic candidates.

Report highlights: 60 pages+ analysis of the field of apoptosis and in particular the various members of the Inhibitor of Apoptosis family (IAP) family pharmaceutical development activity surrounding apoptosis and recent patent activity relating to the IAP family.

About the contributors to this report:

Dr Martin Holcik: Dr Holcik holds a dual position at the Children’s Hospital of Eastern Ontario Research Institute and also as Assistant Professor within the Department of Pediatrics at the University of Ottawa. Dr Holcik has published extensively in the field of apoptosis and has contributed much of the data surrounding one of the most promising targets from this family, Xiap.

Dr Jon Goldhill: Dr Jon Goldhill has over 10 years of academic and industrial research experience including 5 years in middle management at the French pharmaceutical giants, Sanofi-Synthelabo. Focussing on a variety of indications including inflammatory disorders, GI disease, Urological conditions and cancer, Dr Goldhill was responsible for target identification and project development. Dr Goldhill is now CEO and chief analyst at LeadDiscovery and coordinates the identification of candidate drug discovery projects with industrial potential.
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Background
Apoptosis
A general introduction to apoptosis
The "Inhibitor of Apoptosis Proteins" family
Characterization of IAP family members
BIRC1 (Neuronal apoptosis inhibitory protein; NAIP)
BIRC2 (API1; HIAP2; cIAP1; MIHB)
BIRC3 (API2; HIAP1; cIAP2; MIHC)
BIRC4 (XIAP; API3; MIHA; ILP)
BIRC5 (Survivin; API4; TLAP)
BIRC6 (Apollon; BRUCE)
BIRC7 (MLIAP; KIAP; Livin)
BIRC8: (ILP-2; TIAP)
Mechanism of IAP action
Regulation of IAPs
Transcriptional/post-transcriptional control
Post-translational control
IAP regulatory proteins
IAPs in disease
The IAP family as a target for cancer therapy
Epidemiology and treatment options of major cancers
The role of IAPs in the development of cancer
Inhibition of IAPs for the treatment of cancer - strategies and therapeutic response
The IAP family as a target for stroke
Epidemiology and treatment options of stroke
The ischemic cascade
Contribution of apoptosis to the pathogenesis of stroke
The role of IAPs in stroke
Up-regulating IAPs for the treatment of stroke - strategies and therapeutic response
The IAP family as a target for multiple sclerosis
Epidemiology and treatment options of multiple sclerosis
The neuroimmunology of multiple sclerosis
Apoptosis failure as a pathophysiological feature of multiple sclerosis
Involvement of the IAP family in angiogenesis: Implications for both tumor progression and protection against ischemic disease
Market values
An overview of current development activity
Apoptosis stimulators
Trends in apoptosis stimulators
Apoptosis stimulators in development
Profiles of molecules in advanced development
arsenic trioxide
alitretinoin
alitretinoin
CDA-II
exisulind
rubitecan
p53 gene therapy
fenretinide
oblimersen sodium
Unnamed molecules
SDX-101
ceflatonin
Ro-31-7453
epothilone B
brostallicin
T-138067
MX6
CP-461
TLK-286
apomine
hCG
retinoic acid
Urocidin
PCK-3145
LGD-1550
kahalalide F
IL-13-PE38
apolizumab
alvocidib
indisulam
combretastatin A-4
Profiles of IAP-related molecules
HIAP-1 antisense
XIAP inhibitors
AEG-161
Apoptosis inhibitors
Trends in apoptosis inhibitors
Apoptosis inhibitors in development
Profiles of molecules in advanced development
PBI-1402
CPI-1189
DP-b99
IDN-6556
TCH-346
Profiles of IAP-related molecules
IAP gene therapy
Recent patent activity surrounding the IAP family
Strategic summary
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