Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B Cell Malignancies
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02444
Abstract:
Hematopoietic cell kinase (HCK) and Bruton tyrosine kinase (BTK) are critical drivers of survival signaling in MYD88-mutated (MYD88Mut) lymphomas. Building on our previously developed dual HCK/BTK inhibitor KIN-8194, we designed DFCI–002–06, a first-in-class proteolysis-targeting chimera (PROTAC) that potently and selectively degrades both kinases while retaining kinase inhibitory activity with improved selectivity versus KIN-8194. DFCI-002-06 induced enhanced apoptosis in MYD88Mut lymphoma cells and remained active against ibrutinib-resistant BTKCys481 variants. The compound demonstrated high oral bioavailability in mice (F = 39%), favorable pharmacokinetics, and dose-dependent degradation of HCK and BTK in tumors. In TMD8 xenograft models, orally dosed DFCI–002–06 produced superior tumor suppression and prolonged survival compared to KIN-8194. Preclinical safety studies showed a favorable profile, including a negative Ames test, no hERG inhibition at relevant concentrations, and excellent tolerability in a 21 day rat toxicity study. DFCI–002–06 represents a rational dual-target degradation strategy for MYD88Mut lymphomas.
Structure–Activity and Structure–Degradation Relationship Studies of 2-Amino-6-(benzimidazol-2-ylmethyl)-N9-heteroarylpurines as Potent and Selective CDK12/13 Inhibitors and Cyclin K Degraders
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02086
Abstract:
Targeted modulation of the CDK12/CycK complex offers a compelling avenue for exploiting transcriptional addiction in cancer. Among emerging strategies, small molecule CDK12/13 inhibitors that induce selective CycK degradation via proximity-based mechanisms are demonstrating encouraging preclinical results. However, the rational design of molecular glue degraders remains challenging as the structural principles governing efficient target degradation are not always well understood. Here, we report the design, synthesis, structure–activity, and structure–degradation relationship studies of a series of highly potent and selective N9-heteroaryl purine-based CDK12/13 inhibitors, SR-4835 and its optimized analog SR-5037, that act as molecular glue degraders of CycK. In vitro target engagement and in vivo PK/PD studies in mice demonstrate dose-dependent CycK degradation that closely tracks systemic compound exposure. These findings establish CycK as a suitable proximal PD biomarker for this inhibitor class and highlight purine-based scaffolds as a rational framework for the development of bifunctional CDK12/CycK inhibitors and degraders.
The Discovery of RGH-706, a Highly Efficacious MCH1 Receptor Antagonist, for the Treatment of Obesity and Insatiable Hunger
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5c02708
Abstract:
The discovery and characterization of a novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole derivative MCH1 receptor antagonist (37) is disclosed. Starting from our previously investigated pyrazino[1,2-a]indole series and utilizing a scaffold hopping strategy, pyrimidine- and 1,4-diazepine-fused indole derivatives were designed and synthesized. Among these, only the prototype molecule containing the 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole scaffold emerged as a chemically stable and potent MCHR1 antagonist. Previous SAR knowledge coupled with an ex vivo occupancy assay helped us to optimize this advanced lead to our candidate (37). The high MCHR1 potency and excellent receptor occupancy profile of 37 translated into statistically significant body weight loss after 14 days in a DIO mice study, supporting the potential use of this compound as a weight loss agent. Compound 37 (RGH-706) has successfully completed a phase I (SAD & MAD) clinical study in the indication of obesity, followed by an exploratory Phase II study in patients with Prader–Willi Syndrome (PWS).
Discovery of Bis-Acyl Hydrazides as Potent and Bioavailable MTA-Cooperative PRMT5 Inhibitors: A Case Study of Leveraging the Deuterium Kinetic Isotope Effect
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02392
Abstract:
We describe the discovery of a series of potent, selective, and orally bioavailable bis-acyl hydrazide inhibitors targeting the PRMT5·MTA complex for the treatment of MTAP-deleted cancers. Key to this discovery was the identification of major metabolite M1, resulting from N-demethylation of lead inhibitor compound 12, as a potent hERG inhibitor. Leveraging the kinetic isotope effect, we generated methyl-d3 analog 16 which reduced the formation of M1 in vivo, resulting in acceptable safety margins and an improved pharmacokinetic profile. Our data suggest this strategy could be employed more broadly to reduce undesirable metabolism of methylated amines.
