A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose-and timedependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
The RAS/MAPK pathway is a major driver of oncogenesis
and is dysregulated
in approximately 30% of human cancers, primarily by mutations in the
BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1
and ERK2) serve as central nodes within this pathway. The feasibility
of targeting the RAS/MAPK pathway has been demonstrated by the clinical
responses observed through the use of BRAF and MEK inhibitors in BRAF
V600E/K metastatic melanoma; however, resistance frequently develops.
Importantly, ERK1/2 inhibition may have clinical utility in overcoming
acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway
reactivation has occurred, such as relapsed BRAF V600E/K melanoma.
We describe our structure-based design approach leading to the discovery
of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364
exhibits high cellular potency (IC50 = 6 nM) as well as
excellent physicochemical and absorption, distribution, metabolism,
and excretion (ADME) properties and has demonstrated encouraging antitumor
activity in preclinical models.
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
In
one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclinical
studies, we needed a strategy to enable supply of two candidates in
a cost-effective and productive manner. The active pharmaceutical
ingredients (APIs) were structurally complex and were initially obtained
via long linear sequences resulting in time-consuming manufactures.
In addition, both two candidates comprised a biaryl fragment with
hindered rotation along the chiral axis. As a result, a pair of stable
atropisomers was generated for each candidate. With special attention
to the chromatographic challenges for the atropisomer separation and
for the API purification, this article describes our initial efforts
to develop synthetic routes that were amenable for multigram synthesis
of our two drug candidates. In particular, the consequences of implementing
a key Suzuki reaction late or early in the sequence are discussed.
Route
design and proof of concept synthesis was conducted on a
synthetically challenging atropisomeric KRASG12C inhibitor
to support clinical API manufacture. Improvements to the synthesis
of a chiral piperazine fragment gave reduced step count and streamlined
protecting group strategy via the formation and methanol ring opening
of an N-carboxy-anhydride (NCA). The complex atropisomeric
nitroquinoline was accessed via an early stage salt-resolution followed
by a formal two-part nitromethane-carbonylation, avoiding a high temperature
Gould–Jacobs cyclization that previously led to atropisomer
racemization. The substrate scope of the formal nitromethane-carbonylation
strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.
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