Two decades have passed since the rule of five ushered in the concept of "drug-like" properties. Attempts to quantify, correlate, and categorize molecules based on Ro5 parameters evolved into the ...introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examination of oral drug parameters approved before and after the original Ro5 analysis demonstrates that some parameters such as clogP and HBD remained constant while the cutoffs for parameters such as molecular weight and HBA have increased substantially over the past 20 years. The time dependent increase in the molecular weight of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that molecular weight is a "drug-like" property. This analysis does not validate parameters that have not changed as being "drug-like" but instead calls into question the entire hypothesis that "drug-like" properties exist.
Over the past 15years there have been extensive efforts to understand and reduce the high attrition rates of drug candidates with an increased focus on physicochemical properties. The fruits of this ...labor have been the generation of numerous efficiency indices, metric-based rules and visualization tools to help guide medicinal chemists in the design of new compounds with more favorable properties. This deluge of information may have had the unintended consequence of further obfuscating molecular optimizations by the inability of these scoring functions, rules and guides to reach a consensus on when a particular transformation is identified as beneficial. In this manuscript, several composite parameters, or efficiency indices, are examined utilizing theoretical and experimental matched molecular pair analyses in order to understand the basis for how each will perform under varying scenarios of molecular optimizations. In contrast to empirically derived composite parameters based on heavy atom count, lipophilic efficiency (LipE) sets consistent expectations regardless of molecular weight or relative potency and can be used to generate consistent expectations for any matched molecular pair.
Approaches to improve the efficiency of molecular optimizations have received great attention and numerous efficiency metrics have been introduced to assist in this effort. Optimization of properties ...is equally important to optimization of potency and therefore these metrics contain potency versus property calculations. Widespread use of a metric does not guarantee its accuracy and a further understanding of which, if any, metric increases the probability of success was sought. An analysis of LE, LELP and LipE based on theoretical and experimental data was performed demonstrating that LipE most strongly correlates with compound quality as defined by enthalpy-driven binding. The basis for the prioritization of LipE over other metrics in enthalpic optimizations is described.
Two decades have passed since the rule of five ushered in the concept of “drug-like” properties. Attempts to quantify, correlate, and categorize molecules based on Ro5 parameters evolved into the ...introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examination of oral drug parameters approved before and after the original Ro5 analysis demonstrates that some parameters such as clogP and HBD remained constant while the cutoffs for parameters such as molecular weight and HBA have increased substantially over the past 20 years. The time dependent increase in the molecular weight of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that molecular weight is a “drug-like” property. This analysis does not validate parameters that have not changed as being “drug-like” but instead calls into question the entire hypothesis that “drug-like” properties exist.
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an ...important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported ...oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
This paper discusses the relationship between synthesis conditions, crystal morphology, and theoretical modeling of copper and nickel nanoparticles prepared by a modified polyol process. The polyol ...serves as a solvent, a reducing agent, and a capping agent, and we investigate the role several polyol types play in the nucleation and growth of metallic nanoparticles. The nanoparticles are characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Our results demonstrate that changing the solvent system from a short chain polyol (ethylene glycol) to a long chain polyol (tetraethylene glycol) greatly affects the resulting morphology of copper nanoparticles. These results suggest that the polyol is playing a major role as an in situ capping agent and that the various polyol chain lengths in-turn result in various particle morphologies by directly altering the nucleation and growth steps. We were also able to use theoretical modeling to investigate the mechanism for growth to better understand the intermediate structure stability. This work presents an alternative approach in investigating the polyol mechanism by using both theoretical and experimental results and opens new insight for the synthesis of metals and alloys by the polyol process.
To increase the probability of success in drug discovery, the concept of drug-like properties was introduced. Efficiency metrics that normalize potency against these properties could help reach ...drug-like space more efficiently. Potential reasons for the inefficient use of metrics and suboptimal decision making are discussed.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in ...the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro4.5decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
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