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Medicinal Chemistry Open Innovation Doctorates

Final Report Summary - OPENMEDCHEM (Medicinal Chemistry Open Innovation Doctorates)

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1) Project objectives

The ITN-EID project OpenMedchem fosters open innovation collaboration between Industry (GlaxoSmithKline-Diseases of the Developing/GSK-DDW, Tres Cantos, Spain) and Academia (University of Antwerp/UA, Antwerp, Belgium). With a scientific focus on the design and synthesis of innovative antituberculosis drugs, OpenMedChem offers exceptional medicinal chemistry training opportunities to three ESRs. The objectives of the OpenMedChem project are: (1) to design and synthesize a library of novel anti-mycobacterials; (2) to evaluate their anti-tubercular potency; (3) to determine their physico-chemical and DMPK parameters for follow-up studies in mice; and (4) to initiate gross-mode-of-action studies on selected compounds.

2) Performed research and main results

Prior to the initiation of this EID project, GSK-DDW performed a High-Throughput-Screening for antimycobacterial activity within a collection of over 2.106 compounds. Around 1000 confirmed “hits” were identified. The structures of these together with the corresponding antimycobacterial data, were made available to the OpenMedChem ESRs after their appointment at UA. Using bioinformatics approaches, the ESRs clustered the compounds in families and ranked them according
to their antimycobacterial potential and “druglikeness” scores. This allowed the selection of 9 compound families that were considered the most promising within the “hit”-set. Based on all these results, the 5 most promising compound families were retained. In agreement with the GSK-DDW team, each ESR chose one compound family for investigation. The methodology followed by the ESRs combined a systematic, logic-based SAR exploration of the initially identified hit compounds with hybridisation approaches. During the first eighteen months of OpenMedChem, a significant amount of Structure-Activity Relationship (SAR) data was generated for these Families, based on the biological evaluation data of newly synthesized molecules. These SAR data were instrumental for selecting Families I and II as potentially interesting for the synthesis of hybrid compounds. Likewise, the optimal position to introduce a second pharmacophore in the compound topologies of these two
families, was determined based on SAR data. Since in the case of Family III, the SAR data were not able to indicate a suitable derivatisation point, this family was not selected for the construction of hybrid molecules. Enduring cytotoxicity problems encountered with Family III members ultimately led to discarding this family during Month 18. It was replaced by a fourth Compound Family (Family IV). Similar as for the other Compound Families, a relevant body of SAR information was first generated for Family IV via the synthesis and biological evaluation of > 150 novel analogues (situation on 31/10/2016). All three ESRs contributed to the exploration of Family IV. Similarly to Families I-III, the obtained SAR data and in silico modeling were heavily relied on for the determination of the optimal position for introduction of a hybrid coupling partner. Evaluation
data for the first set of hybrid molecules will become available over the next months. Obtained results: For all new compounds that had been prepared on 31/10/2016 (~350 belonging to the four different Compound families and hybrid derivatives therof), the in vitro antimycobacterial potency (MIC) has been determined, along with a set of in vitro physicochemical, biopharmaceutical and toxicological properties. These data are supplemented with target potencies for Compound Families III and IV, for which the mode-of-action could be determined (DHFR inhibition and DprE1 inhibition respectively). The best representatives of each compound family were progressed and subjected to advanced in vitro techniques and/or resistance induction investigations. Based on the corresponding data sets, one representative of Family IV was investigated in vivo in a mouse model of respiratory tuberculosis. This compound displayed a significant antimycobacterial effect in the model, offering proof-of-concept that Family IV has potential for a dedicated lead optimization programme. Additionally, compound Family I was identified as the second most promising class and considered fit for further investigation in order to deliver a robust antimycobacterial lead compound. An overview of the antimycobacterial activity and in vitro biopharmaceutical and physicochemical profiles for Families I-IV and derived hybrid molecules is given in Table 1. As a supplementary experience, the three ESRs were able to work with the industrial partner´s biologists to run an intramacrophage assay (TB bacilli are rapidly taken up by macrophages in humans and other animals) on a selection of their compounds using an advanced confocal microscopy readout. With specific regard to the hybrid antimycobacterials based on compound families I and II, no hybrid compounds could be identified with higher potencies than the best parent molecules. This, together with enduring cytotoxicity problems of Family II members, led to the decision not to further expand this set of compounds. Hybrid compounds based on Family IV are currently under biological evaluation and will be investigated further during the following months.

3) Final results:

-Results with respect to Objective 1 ("To design and synthesize a library of novel anti-mycobacterials"/WP1.1 and WP1.2): A library of >350 novel anti-mycobacterials, including hybrid compounds has been designed and synthesized by the three ESRs as projected in Annex1, implying achievement of this objective.

-Results with respect to Objective 2 and 3 ("To evaluate anti-tubercular potency of the novel compounds" and "To determine their physico-chemical and DMPK parameters for follow-up studies in mice" /WP1.3 WP2.1): anti-tubercular potencies (MIC-values, intracellular activity profiles,...) were determined for all novel compounds. In addition, a full set of physico-chemical and DMPK parameters was determined for all novel compounds, in full accordance with Annex 1, implying achievement of Objectives 2 and 3.

-Results with respect to Objective 4 ("To initiate gross-mode-of-action studies on selected compounds"/WP2.2). The biochemical targets in Mycobacterium tuberculosis for Compound Families III and IV were identified and validated (DHFR and DprE1, respectively). The biochemical target for Compound family I was identified and reported by another research team during the course of the project. Therefore, no additional effort was invested in this by the ESRs. For Compound Family II, we have identified a putative biochemical target (methionine aminopeptidase), results of validation experiments are expected during Q1 2017. Summarizing, Objective 4 has also been achieved.

4) Impact and use:

In line with the project objectives, the generation of a large body of SAR-, physicochemical and in vitro DMPK-data for four new classes of antimycobacterials is of direct use and relevance for the scientific community: highly valuable information has been delivered to guide and streamline ongoing antimycobacterial drug discovery programs both in the pharmaceutical industry and in academia. To date, around 1/3 of all these data have been published in the scientific literature. The remaining part will be published during Q1 and Q2 of 2017. Based on all these in vitro data, one representative of Family IV has also been investigated in an in vivo mouse model of respiratory tuberculosis. This experiment delivered proof-of-concept that Family IV has potential for a dedicated lead optimization programme. Additionally, compound Family I was identified as the second most promising class and considered fit for further investigation in order to deliver a robust antimycobacterial lead compound. The identification of compound families that create direct potential for drug development is also relevant for society at large, for which tuberculosis is currently one of the main and most deadly infectious disease threats. Again, publication of all research data (in line with the Open Innovation mission of OpenMedChem) will allow the scientific community and society to benefit from the results of this project.