Prediction of active human dose: learnings from 20 years of Merck KGaA experience, illustrated by case studies

Peters, Sheila Annie; Petersson, Carl; Blaukat, Andree; Halle, Joern-Peter; Dolgos, Hugues

doi:10.1016/j.drudis.2020.01.002

Cited by 15 publications

(15 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The more complete tumor growth regression observed with TPX-0131 treatment may be due to the 260-fold greater cellular potency of TPX-0131 relative to lorlatinib (Table 2). Absolute potencynot just the potency relative to inhibitor exposuremay contribute toward overall in vivo efficacy due to timedependent changes in target engagement in the dynamic environment of the human body where both drug and target concentrations vary as a function of time (18)(19)(20). In addition to superior potency against the G1202R solvent front mutation, TPX-0131 is more potent than previous generations of ALK inhibitors against wild-type ALK and ALK point mutations ( the L1196M gatekeeper mutation, TPX-0131 is 76-fold more potent than lorlatinib and 11-to 550-fold more potent than the first two generations of inhibitors.…”

Section: Discussionmentioning

confidence: 99%

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations

Murray¹,

Zhai²,

Deng³

et al. 2021

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of CNS penetration and potency against wild-type ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATPbinding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against wild-type ALK and many types of ALK resistance mutations, e.g. G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC 50 <10 nmol/L) wild-type ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations

Murray¹,

Zhai²,

Deng³

et al. 2021

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…In the case of GKMs, repotrectinib was 140 -430-fold more potent than selitrectinib, whereas differences were more variable for SFMs, with 11-to 95-fold differences. Absolute potency of an inhibitor may be important because it can contribute to overall in vivo efficacy through time-dependent target engagement in an environment where both drug and target concentrations vary as a function of time (25)(26)(27). Interestingly, the TRK protein context (e.g., TRKA vs TRKB vs TRKC) was found to have little effect on inhibitor potency with the exception of the GKMs.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations

Murray¹,

Rogers²,

Zhai³

et al. 2021

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib, entrectinib) but often mutate, limiting the durability of response for NTRK+ patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib, selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Co-crystal structures of repotrectinib with wild-type TRKA and the TRKA G595R SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA-NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM+SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK+ cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first-and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.

show abstract

“…All compounds in addition to 1 showed 10−30-fold weaker potency against the murine MMP-13 enzyme, indicating an additional potency/PK burden in robustly challenging the drug concept in murine models in vivo. 19 Finally, compounds had low aqueous solubility at pH 4.5 and high solubility at neutral pH as expected for carboxylates.…”

Section: ■ Introductionmentioning

confidence: 90%

“…All compounds showed a >5-fold activity shift in the presence of human serum, however, suggesting that the class would have high protein binding and low free fraction in vivo. All compounds in addition to 1 showed 10–30-fold weaker potency against the murine MMP-13 enzyme, indicating an additional potency/PK burden in robustly challenging the drug concept in murine models in vivo . Finally, compounds had low aqueous solubility at pH 4.5 and high solubility at neutral pH as expected for carboxylates.…”

Section: Introductionmentioning

confidence: 92%

Indole Inhibitors of MMP-13 for Arthritic Disorders

et al. 2021

View full text Add to dashboard Cite

Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.

show abstract

Prediction of active human dose: learnings from 20 years of Merck KGaA experience, illustrated by case studies

Cited by 15 publications

References 41 publications

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations

Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations

Indole Inhibitors of MMP-13 for Arthritic Disorders

Contact Info

Product

Resources

About