Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR

Petros, Andrew M.; Huth, Jeffrey R.; Oost, Thorsten; Park, Cheol‐Min; Ding, Hong; Wang, Xilu; Zhang, Haichao; Nimmer, Paul; Mendoza, Renaldo; Sun, Chaohong; Mack, J.; Walter, Karl A.; Dorwin, Sarah A.; Gramling, Emily; Ladror, Uri S.; Rosenberg, Saul H.; Elmore, Steven W.; Fesik, Stephen W.; Hajduk, Philip J.

doi:10.1016/j.bmcl.2010.09.033

Cited by 65 publications

(51 citation statements)

References 9 publications

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“…It will be interesting to see whether deletion of Mcl-1 and Bcl-2 in megakaryocytes results in a similar phenotype. Given that agents specifically targeting Bcl-2 family prosurvival proteins are currently being developed for use in a range of human malignancies (Leber et al, 2010;Petros et al, 2010;Wilson et al, 2010;Roberts et al, In Press), it will be important to understand the contribution they make to the development and survival of the megakaryocyte lineage. (Lindsten et al, 2000), Bax (Knudson et al, 1995) and Bcl-x (Motoyama et al, 1999) knockout, Bcl-x (Rucker et al, 2000 and Bax (Takeuchi et al, 2005) floxed, Pf4-Cre (Tiedt et al, 2007), and UBC-GFP (Schaefer et al, 2001) transgenic mice have been previously described.…”

Section: Discussionmentioning

confidence: 99%

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Josefsson¹,

James²,

Henley³

et al. 2011

J Cell Biol

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It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic-or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-x L resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak / Bax / hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.

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Section: Discussionmentioning

confidence: 99%

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Josefsson¹,

James²,

Henley³

et al. 2011

J Cell Biol

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“…X-ray crystallography of linked compound also revealed that it displays similar binding mode as two initial fragments. In another study, Petros et al [110] identified through fragment linking approach a highly potent Bcl-2 inhibitor that was 1000 fold selective for Bcl-2 over Bcl-xL. They started with a less potent and moderately selective compound identified from proteindetected NMR screen of 17000 fragments.…”

Section: Fragment Linkingmentioning

confidence: 95%

“…Fragment linking was first successfully demonstrated by Fesik and co-workers in their "SAR by NMR" paper [12]. Since then, the fragment linking approach has been used by a number of groups [100,[105][106][107][108][109][110][111][112] to link two weak affinity fragments to obtain highly potent compound. One of these studies describes linking two low affinity fragments identified from a fragment screen against Hsp90 [111] to obtain a compound with 1000 fold higher affinity than initial fragments against Hsp90 while maintaining LE.…”

Section: Fragment Linkingmentioning

confidence: 98%

Fragment Based Drug Design: From Experimental to Computational Approaches

Kumar

Voet²,

Zhang

2012

CMC

151

102

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Fragment based drug design has emerged as an effective alternative to high throughput screening for the identification of lead compounds in drug discovery in the past fifteen years. Fragment based screening and optimization methods have achieved credible success in many drug discovery projects with one approved drug and many more compounds in clinical trials. The fragment based drug design starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The weak affinity of fragments for their target requires the use of biophysical techniques such as nuclear magnetic resonance, X-ray crystallography or surface plasmon resonance to identify hits. These techniques are very sensitive and some of them provide detailed protein fragment interaction information that is important for fragment to lead optimization. Despite the huge advances in technology in the past years, experimental methods of fragment screening suffer several challenges such as low throughput, high cost of instruments and experiments, high protein and fragment concentration requirements. To address challenges posed by experimental screening approaches, computational methods were developed that play an important role in fragment library design, fragment screening and optimization of initial fragment hits. The computational approaches of fragment screening and optimization are most useful when they are used in combination with experimental approaches. The use of virtual fragment based screening in combination with experimental methods has fostered the application of fragment based drug design to important biological targets including protein-protein interactions and membrane proteins such as GPCRs. This review provides an overview of experimental and computational screening approaches used in fragment based drug discovery with an emphasis on recent successes achieved in discovering potent lead molecules using these approaches.

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“…The deep and large hydrophobic BH3-binding groove of the Bcl-2 family members necessitates that small molecules occupying the space are hydrophobic and have high molecular weight (Park et al, 2006;Petros et al, 2006;Petros et al, 2010). Therefore, the physicochemical properties of both the BH3 mimetics navitoclax and ABT-199 (Table 1) do not conform to the "Lipinski rule of 5" (Lipinski et al, 2001), and it would be predicted that both compounds have low bioavailability after oral dosing.…”

Section: Introductionmentioning

confidence: 99%

The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

et al. 2013

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Navitoclax (ABT-263), a Bcl-2 family inhibitor and ABT-199, a Bcl-2 selective inhibitor, are high molecular weight, high logP molecules that show low solubility in aqueous media. While these properties are associated with low oral bioavailability (F), both navitoclax and ABT-199 showed moderate F in preclinical species. The objective of the described study was to determine if lymphatic transport contributes to the systemic availability of navitoclax and ABT-199 in dogs. The intravenous pharmacokinetics of navitoclax and ABT-199 were determined in intact (noncannulated) dogs. In oral studies, tablets (100 mg) of navitoclax and ABT-199 were administered to both intact and thoracic lymph duct-cannulated (TDC) dogs. The clearance of navitoclax and ABT-199 was low; 0.673 and 0.779 ml/min per kilogram, respectively. The volume of distribution of both compounds was low (0.5-0.7 l/kg). The half-lives of navitoclax and ABT-199 were 22.2 and 12.9 hours, respectively. The F of navitoclax and ABT-199 were 56.5 and 38.8%, respectively, in fed intact dogs. In fed TDC dogs, 13.5 and 4.67% of the total navitoclax and ABT-199 doses were observed in lymph with the % F of navitoclax and ABT-199 of 21.7 and 20.2%, respectively. The lower lymphatic transport of ABT-199 corresponds to the lower overall % F of ABT-199 versus navitoclax despite similar systemic availability via the portal vein (similar % F in TDC animals). This is consistent with the higher long chain triglyceride solubility of navitoclax (9.2 mg/ml) versus ABT-199 (2.2 mg/ml). In fasted TDC animals, lymph transport of navitoclax and ABT-199 decreased by 1.8-fold and 10-fold, respectively.

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Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR

Cited by 65 publications

References 9 publications

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Fragment Based Drug Design: From Experimental to Computational Approaches

The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

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